Open access peer-reviewed chapter

Innate Immunity and Neuroinflammation in Neuropsychiatric Conditions Including Autism Spectrum Disorders: Role of Innate Immune Memory

Written By

Harumi Jyonouchi

Submitted: December 10th, 2018 Reviewed: May 31st, 2019 Published: July 4th, 2019

DOI: 10.5772/intechopen.87167

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Abstract

The neuroimmune network represents a dense network of multiple signals mediated by neurotransmitters, hormones, growth factors, and cytokines produced by multiple lineage cells and is crucial for maintaining neuroimmune homeostasis. Endogenous and exogenous stimuli, which are dangerous to the body, are detected by sensor cells, and they rapidly inform the brain through this network. Innate immunity is thought to play a major role in the neuroimmune network, through cytokines and other mediators released from secretary innate immune cells. Recent research has revealed that innate immunity has its own memory. This is accomplished by metabolic and epigenetic changes. Such changes may result in augmenting immune protection with a risk of excessive inflammatory responses to subsequent stimuli (trained immunity). Alternatively, innate immune memory can induce suppressive effects (tolerance), which may impose a risk of impaired immune defense. Innate immune memory affects the neuroimmune network for a prolonged period, and dysregulated innate immune memory has been implicated with pathogenesis of neuropsychiatric conditions. This chapter summarizes a role of innate immune memory (trained immunity vs. tolerance) in neuroinflammation in association with neuropsychiatric conditions including autism spectrum disorders (ASD).

Keywords

  • innate immunity
  • cytokines
  • neuroinflammation
  • neuroimmune network
  • immune metabolic processes

1. Introduction

It is well accepted that inflammation in the peripheral organs can influence homeostasis and immune responses in the central nervous system (CNS) [1]. In common neuropsychiatric conditions such as schizophrenia and depression, evidence indicates that neuroinflammation plays a role in the disease pathogenesis [2]. Long-lasting effects of neuroinflammation in such neuropsychiatric conditions are implicated with altered innate immune responses in the absence of specific pathogens [2]. However, until recently, it is not well understood how innate immunity, which was thought to have no lasting memory unlike adaptive immunity, can exert prolonged actions on the CNS. The recent discovery of innate immune memory (trained immunity vs. tolerance) shed a light in a long postulated role of innate immunity in neuropsychiatric diseases [3, 4].

Since the existence of the immune system was recognized more than 50 years ago, the immune system has been thought to be comprised of two components, innate immunity and adaptive immunity. Innate immunity is the arm that mounts nonspecific, acute immune responses, by sensing microbial by-products called pathogen-associated molecular patterns (PAMPs) or by-products derived from tissue injuries called damage-associated molecular patterns (DAMPs) [5]. Signaling through PAMPs and DAMPs are thought to play a major role in plant immunity [6]. In animals, adaptive immunity is the arm that develops antigen (Ag)-specific responses. The development of Ag-specific responses requires lengthy processes including antigen (Ag) processing by Ag-presenting cells (APCs), Ag presentation to T and B cells, and TCR or immunoglobulin gene arrangements of T and B lymphocytes, respectively, which lead to the development of Ag-specific T and B cells and finally antibodies (Abs) [7]. Adaptive immunity effectively eliminates hazards from the body through Ag-specific cellular and humoral immune responses [7]. Adaptive immunity results in the development of long-lasting Ag-specific memory T/B cells [8]. In this way, the body retains immune memory against specific pathogens for a prolonged time. It is well known that individuals who have survived measles will retain measles-specific immune defense for life.

In contrast, immunology textbooks have long taught us that innate immunity does not have any lasting effects or memory, and it is mainly effective in containing infection until adaptive immunity takes over. Innate immunity has also been known to shape adaptive immunity through multiple mechanisms such as affecting actions of APCs, thereby indirectly modifying adaptive immune responses [7]. However, recent exciting research revealed that innate immunity can have its own memory, following an immune stimulus, and this depends on time, amount, and the kinds of stimuli through metabolic and epigenetic changes [3, 9]. More importantly, the stimuli that evoke innate immune memory are not restricted to microbes; nonpathogenic challenges such as stress and obesity are also found to cause innate immune memory [3, 10].

As described previously, despite the accumulating evidence, it was difficult to understand how innate immunity exerts lasting effects, in the absence of specific pathogens or other persistent environmental stimuli, in neuropsychiatric conditions. The recognition of innate immune memory (trained immunity vs. tolerance) has provided us new insights with regard to the role of innate immunity in physiological as well as pathogenic consequences in the brain. In this chapter, research efforts shaping a concept of innate immune memory (trained immunity vs. innate immune tolerance) will be discussed first. In the latter part of the chapter, a potential role of innate immune memory in neuropsychiatric conditions, especially in ASD, will be discussed.

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2. Innate immune memory

2.1 Trained immunity

The presence of innate immune memory was first suspected because of unexpected, nonspecific effects of vaccinations. This is best known for a Bacillus Calmette-Guérin (BCG) vaccine. Epidemiological studies and subsequent randomized trials showed that the BCG vaccination not only provided protection for tuberculosis but also protection against other pathogens, especially those causing respiratory infection, which resulted in a reduction in infant mortality greater than expected for reducing tuberculosis-associated mortality [11, 12]. Likewise, the measles vaccination resulted in a striking reduction in children’s mortality, which was again not to be explained by the reduction in mortality caused by measles [11]. These epidemiological observations were further explored by researchers in the Netherlands. They first demonstrated that innate immune memory does exist in animal models [13]. Namely, these researchers showed that BCG provided enhanced protection against Candida albicansthrough nonspecific adaptation of innate immunity, independent of lymphocytes [13]. They proposed to name this process of innate immune memory “trained immunity.” The following studies by the same group also revealed that such adaptive changes in innate immunity are present not only in monocyte-macrophage lineage cells but also in other innate immune cells such as natural killer (NK) cells [14] and progenitor cells of innate immune cells in the bone marrow [15, 16]. Further studies revealed the presence of trained immunity in humans [17, 18, 19]. It became clear that trained immunity is similar to plant immunity which does not develop Ag-specific immunity, but develops prolonged immune defense by metabolic and epigenetic modulation [20]. Mounting evidence has now repeatedly shown that trained immunity is Ag nonspecific; the second stimulus (DAMP or PAMP) causing innate immune activation can be different from the first stimulus [3].

2.2 Mechanisms of trained immunity

Adaptive changes observed in “in vitro” models of trained immunity with β-glucan, a representative PAMP from Candida albicans, have been extensively studied. It was revealed that ß-glucan treatment induces activation of the dectin-1/Akt/PTEN/mTOR/HIF-1α signaling pathway in innate immune cells [21]. That is, β-glucan activates dectin-1 which recruits Akt, leading to activation of mammalian target of rapamycin (mTOR) with suppression of PTEN expression and phosphorylation of the tuberous sclerosis complex (TSC) [22]. Activation of this pathway switches cellular metabolism from oxidative phosphorylation (ATP synthesis) to glycolysis, thereby reducing basal cellular respiration and increasing in glucose consumption, resulting in higher production of lactate [21]. Such metabolic changes lead to the exportation of citrate to the cytoplasm for cholesterol synthesis and phospholipid synthesis [23, 24].

This metabolic shift described above results in the replenishment of the Krebs cycle by metabolization of glutamine into glutamate and α-keto-glutamate, leading to an accumulation of fumarate [23, 24]. Higher concentration of fumarate inhibits the KDM5 family of H3K4 demethylase that eventually leads to epigenetic reprogramming [23]. It has been reported that in the initial phase of trained immunity, lysine 27 of histone 3 (H3K27) is acetylated and lysine 4 of histone 3 (H3K4) is methylated rapidly [25]. Although H3K27Ac gradually returns to the baseline over time, H3K4me3 was found to remain elevated in the trained immunity [25]. Such epigenetic histone modification (accumulation of H3K4me3) is known to lead to the remodeling of the local chromatin into an open and accessible state, resulting in the facilitation of the loading of transcriptional machinery. The remaining accumulation of H3K4me3 on chromatin has been implicated in the establishment of the epigenetic memory in the trained immunity [25, 26]. It was hypothesized that H3K4me3 increases the local hydrophobicity of the chromatin, allowing for liquid-liquid phase separated transcription factors to engage with the DNA in the aqueous environment of the nucleus, subsequently rendering loading of transcriptional machinery onto promoters [27, 28, 29]. This will allow cells to start rapid transcription of the genes necessary for immune responses, thereby causing a much stronger Ag nonspecific pro-inflammatory response.

Long noncoding RNAs (lncRNAs) can function as a molecular scaffold where multiple protein complexes can assemble, and they also guide these complexes to specific gene loci [30]. Recent research disclosed a new class of lncRNAs named immune gene-priming lncRNAs (IPLs), and IPLs were found to have a crucial role in the accumulation of H3K4me3 on chromatin [31]. A candidate IPL, termed upstream master lncRNA of the inflammatory chemokine locus (UMLILO), was found to be crucial for trained immunity; ablation of the UMLILO transcript abolished β-glucan-induced trained immunity in both human and murine monocytes [30].

As shown in epidemiological studies of vaccinations, trained immunity, caused by metabolic and epigenetic changes, will be beneficial in providing broader immune defense and promoting tissue repair [32]. On the other hand, maladapted trained immunity can be detrimental to human health. Chronic inflammatory conditions including neuropsychiatric conditions have been implicated with maladapted changes in trained immunity [2, 9]. It should also be noted that induction of trained immunity appears to be associated with doses of PAMP, perhaps DAMP in humans; depending on the dose and the kinds of PAMP/DAMP, tolerance can be induced, instead of trained immunity [2]. It has been shown that low to moderate doses of β-glucan, tri-DAP, and muramyl dipeptides are reported to induce trained immunity [33]. It also needs to be cautioned that the effects of trained immunity are likely associated with individual’s genetic and epigenetic background. For example, nonspecific effects of infant BCG vaccination are reported to be heterogeneous, affected by multiple genetic and environmental factors including age, gender, interactions with other vaccines, and exposure to infectious pathogens at the time of BCG vaccination [34].

2.3 Mediators of trained immunity

It has been reported that pre-administration of pro-inflammatory innate cytokines [interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-6] provided protection against a variety of microbes [35]. Among the cytokines administered, IL-1 showed superior effects over TNF-α or IL-6 [35]. In BCG-vaccinated individuals, increase in production of these innate cytokines by monocytes in response to other microbes, other than BCG, was also found; this effect was again the most dependent on IL-1β [32]. IL-1β has also been reported to be crucial in the induction of trained immunity in NK cells [36]. On the other hand, in individuals with chronic mucocutaneous candidiasis, STAT-1-mediated type II interferon (IFN) induction was found to be crucial for induction of trained immunity [37]. The role of type II IFN (IFN-γ) in animal models was also reported by Kaufmann et al. [16]. However, in humans, innate immunity-associated protection (trained immunity) has been mainly implicated with IL-1β and other IL-1 families [38].

As detailed in the previous section, a metabolic shift from oxidative phosphorylation to aerobic glycolysis through the Hypoxia inducible factor-1α (HIF-1α) pathway downstream to mTOR is crucial for the development of trained immunity, since inhibition of this pathway is abolished induction of trained immunity [21]. Namely, in HIF-1α knockout mice, trained immunity was not induced [21]. IL-1β is known to be a direct target of HIF-1α [39], having a HIF-1α binding site in the promoter region of IL-1β gene [40]. It is now thus proposed that HIF-1α-induced IL-1β also plays a role in epigenetic changes, through histone modifications [35]. Alternatively, IL-1β has been shown to upregulate HIF-1α [41].

Given the role of IL-1β in trained immunity, excessive, dysregulated production of IL-1β is likely to cause maladapted trained immunity and resultant pathogenic consequences. This may be observed in patients with autoinflammatory syndromes associated with gene mutation that lead to overproduction of IL-1β, including cryopyrin associated periodic syndrome (CAPS) [38, 42]. On the other hand, impaired induction of trained immunity can also cause detrimental effects. It was reported that patients with chronic mucocutaneous candidiasis exhibit impaired induction of STAT-1-dependent, trained immunity in response to β-glucan [37].

The above-described metabolic shift is not limited to glucose metabolism. Changes in glutamine and cholesterol metabolism have also shown to be crucial in trained immunity [24]. Consequently, it is thought that increased cholesterol content also plays a role in the development of trained immunity. Interestingly, increased levels of oxidized low-density lipoprotein (OxLDL) caused by dysregulated cholesterol metabolism are found to induce trained immunity in human monocytes [10]. Such a finding indicates a pathogenic role for maladapted trained immunity in atherosclerosis, since monocyte and macrophage cells are known to play a major role in plaque formation in vascular endothelium, a major histologic change in atherosclerosis [10].

2.4 Tolerance in innate immunity

As detailed in the previous section, trained immunity causes a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, rendering macrophage and monocyte lineage cells to classically activated cells or M1 phenotype; these cells exhibit impaired OXPHOS and anabolic repurposing of the tricarboxylic acid (TCA) cycle [43, 44]. In contrast, alternatively activated or the M2 phenotype of macrophages and monocytes has balanced processes of OXPHOS and TCA cycle activation; enhanced glycolytic generation of pyruvate fuels the TCA cycle, paralleling the induction of OXPHOS [44]. Trained macrophages via ß-glucan exposure are shown to reveal M1 phenotype [21]. Generation of M1 vs. M2 phenotypes of macrophages indicates the importance of regulating innate immune responses for prevention of excessive, potentially harmful inflammatory responses. In addition to generation of M2 phenotype, hypo-responsiveness of innate immunity has been described as endotoxin tolerance and compensatory anti-inflammatory response syndrome (CARS) [45]. Such regulatory mechanisms also have lasting effects, as observed in trained immunity.

Endotoxin tolerance in innate immunity was first shown in rodent models of sepsis. Namely, survival from sepsis is associated with diminished or absence of responses to LPS, an endotoxin [46]. Subsequently, it was shown that previous exposure to a sublethal dose of LPS led to resistance to a lethal dose of LPS in rodents [46]. Endotoxin tolerance is thought to be a result of innate immune memory with lasting immune hypo-responsiveness, even to non-LPS stimulants [47]. Phenotypic changes of tolerant innate immune cells are characterized with less production of inflammatory cytokines (TNF-α, IL-12, IL-6) and increase in production of counter-regulatory cytokines (IL-10 and TGF-β) upon stimulation [48, 49]. CARS was recognized as a clinical syndrome which is thought to represent a phase of immune “exhaustion,” following initial potent immune activation, known as systemic inflammatory response syndrome (SIRS) [50]. Peripheral blood monocytes and neutrophils from CARS patients are reported to reveal similar phenotype to endotoxin-tolerant cells observed in rodent models [45, 49]. Recent research revealed that persistent effects of endotoxin tolerance and CARS are mediated by lncRNAs as well as microRNAs (miRNAs).

LPS activates TLR4 which leads to the activation of the myeloid differentiation factor 88 (MyD88)-mediated pathway and the TIR-domain-containing adaptor-inducing interferon-β (TRIF) pathway [45]. The molecular signature of endotoxin tolerance involves downregulation of TLR4, decreased recruitment of MyD88 or TRIF to TLR4, decreased activation of IL-1 receptor-associated kinase (IRAK)1 and IRAK4, diminished nuclear factor κ chain of B-cell (NF-κB) signaling, as well as upregulation of negative regulatory molecules including SH2 domain-containing inositol phosphatase 1 (SHIP1) [51].

2.5 Regulators of innate immune tolerance

Recent research revealed a role of miRNAs in the regulation of endotoxin tolerance. Specifically, miR-155 and miR-146α have been shown to regulate endotoxin tolerance [52]. MiR-146α reduces TLR signaling, by targeting IRAK1 and TRAF6, key components of TLR signaling pathway [53]. In contrast, miR-155 is reported to inhibit expression of SHIP1 and SOCS1, negative regulators of TLR signaling, prohibiting or attenuating tolerance induction by endotoxin [54, 55]. Several other miRNAs are also implicated with regulation of endotoxin intolerance [45]. It was shown recently that miR-221/miR-222 regulates functional reprogramming of macrophages during LPS-induced tolerization [47]. miR-221/miR-222 targets brahma-regulated gene 1 (Brg1), rendering transcriptional silencing of a subset of inflammatory genes that depend on SWI/SNF and STAT-mediated chromatin remodeling [47].

Recent research also revealed a role of lncRNAs in endotoxin tolerance; lncRNAs exert transcriptional, posttranscriptional, and translational regulation of gene expression [56, 57, 58]. Multiple lncRNAs are reported to regulate target molecules of TLR4 signaling pathways. LPS-responsive lncRNAs Mirt2, THRIl, MALTAT1, NKILA, lincRNA-21, and SeT have been reported to suppress expression of pro-inflammatory mediators including TNF-α [45]. For example, Mirt2 is reported to inhibit TRAF6 ubiquitination, leading to a decrease in TNF-α production [59]. However, at this time, relationships between actions of miRNAs and lncRNA in innate immune tolerance are not well understood. Other soluble mediators such as cytokines (IL-1β, IL-10, TGF-β, and TNF-α) are also reported to induce cross-tolerance or cytokine-mediated tolerance, causing a signaling cascade similar to that observed in TLR signaling [60]. In contrast, interferons (IFN-γ, α2-IFN, etc.) are known to abrogate endotoxin tolerance [61, 62]. Again these soluble mediators exert their actions on endotoxin tolerance via modulation of intracellular lncRNAs [45].

This type of innate immune memory (tolerance) is thought to be important in maintaining brain homeostasis, and impaired tolerance of innate immunity has been suspected in chronic neurodegenerative conditions such as Alzheimer’s disease [9]. Aging is associated with an increased load of gram-negative bacteria in the GI tract and mouth mucosa, resulting in an increase in endotoxin levels in the blood and the brain [62]. However, aging individuals tolerate higher LPS levels in the brain through developing endotoxin tolerance [63].

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3. Role of innate immunity in the nervous system

It is known that innate immunity does exist in the brain, playing a crucial role in brain morphogenesis and homeostasis. The major innate immune cells in the central nervous system (CNS) are microglial cells which are endogenously generated in the brain, but they can also be developed from bone marrow-derived monocytes, which are called BM-derived microglial cells (BMDM) [64, 65]. BMDM-induced inflammation has been implicated in neuropsychiatric conditions [64, 65]. It has also been reported that peripherally derived macrophages modulate microglial function after CNS injury; in this case, they are reported to exert anti-inflammatory effects [66]. Other innate immune cells in the CNS such as astrocytes are also known to exert important physiological roles [9, 67].

3.1 Trained immunity in the CNS

Inflammation in the periphery can prompt immune responses in the brain [1, 4]. Given the effects of trained immunity (activation vs. tolerance) in rodent models and humans, the development of maladapted innate immune memory in the CNS is expected to result in undesired, hazardous effects to the brain. However, reports concerning the effects of trained immunity and/or innate immune tolerance in the brain have been limited. Nevertheless, it was shown that microglial cells isolated from adult rats that were exposed to E. coliduring the newborn period had increased expression of IL-1β mRNA [68]. The rats exposed to E. colias newborns were also found to have impaired memory when they were challenged with a low dose of LPS, which was blocked by minocycline [2]. In experiments employing microglial cells obtained from sheep fetuses whose mother was given LPS intravenously, these fetal microglial cells were shown to have metabolic and epigenetic modulation, as has been reported in trained immunity [69].

Independent of the studies concerning trained immunity in the brain, persistent effects of maternal immune activation (MIA) on fetuses have been extensively studied, as one of the best studied rodent models of ASD [70]. In this model, sterile inflammation in pregnant rodents was induced with the use of PAMPs such as LPS, poly I:C, resulting in impaired neuropsychiatric symptoms in offspring in their adult years [70]. That is, offspring of MIA mothers have been shown to suffer from persistent behavioral symptoms and cognitive deficits frequently seen in ASD subjects later in life [70]. In addition, MIA also causes persistent alteration of adaptive immunity [71]. However, in this model, it is not yet well understood how innate immune memory (most likely trained immunity in this model) plays a role in a MIA model, causing persistent behavioral changes and impaired cognitive development. Children exposed to stressful events during the fetal and newborn period have also been reported to have higher levels of pro-inflammatory cytokines and neurodevelopmental impairment than control children [2]. Given the research findings in molecular mechanisms of trained immunity described in the previous section, there is a possibility that maladapted trained immunity contributes to the onset and progress of some neuropsychiatric disorders.

3.2 Innate tolerance in the brain

Tolerized innate immunity in the brain is thought to be crucial for limiting excessive inflammatory responses during brain tissue repair that involves phagocytosis of apoptotic cells and damaged tissue debris by tolerant phagocytes [72]. In rodent models, disruption of this pathway leads to neuroinflammation and subsequent neuronal damage [73]. An important regulator of this pathway is the triggering receptor expressed on myeloid cells 2 (TREM-2), which is expressed on microglial cells [74]. Blockade of TREM-2 was shown to exacerbate experimental autoimmune encephalitis (EAE), a rodent model of multiple sclerosis (MS) [75]. Apolipoprotein E (ApoE) which is a TREM-2 ligand was shown to have a role in maintaining tolerized phenotype of phagocytic cells [74]. This interaction was found to be impaired in patients with Alzheimer’s disease [9]. In animal models of Alzheimer’s disease treated with trained immunity vs. tolerance inducing stimuli, it was reported that long-term modulation of brain immune responses were observed, and the authors attributed this prolonged effects on innate immune memory to reprogramming of microglial cells [4].

3.3 mTOR-related pathology in neuropsychiatric disorders

In the previous section describing molecular pathways associated with trained immunity, the importance of mTOR signaling has been repeatedly shown. One thing we learned from the research on trained immunity is that multiple lineage cells reveal metabolic and epigenetic reprogramming in the process of innate immune memory, which, in animal models, can also be applied to microglial cells [4]. Interestingly, brain dysfunction caused by dysregulated mTOR signaling has been implicated in several neuropsychiatric disorders. In the next paragraph, we summarize mTOR-related brain dysfunctions and proposed mechanisms.

One of the expected consequences of excessive mTOR signaling caused by trained immunity is the impairment of lysosomal degradation of intracellular components, since mTOR activation inhibits autophagy via inhibition of the early steps of autophagosome biogenesis [76, 77]. Autophagy is a key physiological cellular function that clears intracellular molecules and thought to be developed to adjust the state of nutrient depletion [76, 77]. However, this is also an important mechanism to remove misfolded proteins that naturally occur in living cells [22]. In addition to degradation of misfolded proteins, autophagy also degrades altered subcellular organelles, such as the mitochondria [22]. Prolonged dysfunction in autophagy can lead to detrimental effects and is implicated in the pathogenesis of multiple neuropsychiatric conditions including dementia, movement disorders, seizures, brain ischemia, ASD, affective disorder, and schizophrenia [78, 79, 80, 81, 82]. In rodent models of depression, tuberous sclerosis, and ASD, rapamycin (sirolimus), a representative mTOR inhibitor, has been shown to attenuate social interactions and reverse behavioral effects on their neuropsychiatric symptoms [83, 84, 85, 86]. Thus metabolic and epigenetic changes caused by trained immunity may have profound effects through altered levels of autophagy, as a result of metabolic and epigenetic reprograming, as detailed in the previous section.

3.4 ASD and a possible role of trained immunity

In this section, we discuss a possible role for trained immunity in the onset and progress of ASD. As a clinician, the author observed that an apparent strong immune stimulus altered the responses to subsequent immune stimuli in some, but not all ASD children and these ASD children also exhibit fluctuating neuropsychiatric symptoms, following microbial infection [87, 88]. As discussed in the previous section, in the MIA model of ASD, prolonged effects of MIA on the offspring brain can be explained through a concept of trained immunity occurring to the fetus at the time of sterile immune activation in the mother. This may have also happened in ASD subjects as described above. However, it should be noted that ASD is a behaviorally defined syndrome, diagnosed on the basis of behavioral symptoms, except for a minority of ASD cases that have well-defined gene mutations [89]. Therefore, based on the author’s clinical experience, it is likely that trained immunity plays a role in a subset of ASD subjects for whom neuroinflammation is associated in their ASD pathogenesis.

In ASD patients, just like in other neuropsychiatric conditions, a role of inflammation has been long suspected, and more and more evidence has been accumulating [90, 91, 92]. In the research of innate immune abnormalities in ASD children, we have also found evidence of dysregulated innate immune responses, shifting to pro-inflammatory responses in a subset of ASD subjects [88, 93, 94]. We also experienced that these ASD subjects suffer from various comorbid medical conditions involving the gastrointestinal (GI) tract and other organs [87]. Retrospectively, our findings may be reflecting maladapted innate immunity as a form of trained immunity in such ASD subjects; these ASD subjects may fall into an ASD subset which we have called inflammatory autism, mimicking the rodent ASD model of MIA [93]. Our previous findings that may indicate altered innate immune memory in such ASD patients are as follows:

  • In some but not all the ASD subjects, we found significant changes in innate immune abnormalities which are best reflected in changes in IL-1β/IL-10 ratios produced by purified peripheral blood monocytes (PBMo) [88, 93]. Namely, some patients reveal high ratios of IL-1β/IL-10, while others showed low ratios, and these rations can change from time to time, depending on their exposure to immune insults [93].

  • ASD subjects who revealed high and/or low IL-1β/IL-10 ratios also revealed fluctuating behavioral symptoms following immune insults [94]. Parents of these subjects often describe more severe, prolonged illnesses and frequent respiratory infection following microbial infection [87]. They also seem to reveal significant changes in their behavioral symptoms and cognitive activity with immune stimuli not associated with microbial infection; these ASD children may exhibit worsening neuropsychiatric symptoms, following flare-ups of aeroallergen allergy, delayed-type food allergy, and adverse reactions to medications including vaccinations [87, 94].

  • ASD subjects who revealed high and/or low IL-1β/IL-10 ratios also revealed changes in production of inflammatory monocyte cytokines including TNF-α and IL-6 [93, 95].

  • PBMo from ASD subjects who revealed altered IL-1β/IL-10 ratios also revealed changes in miRNA expression by PBMo, as compared to cells obtained from neurotypical, non-ASD controls [93].

  • We also studied changes in mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) obtained from ASD subjects and non-ASD controls. Our results revealed evidence of altered mitochondrial respiration in association with changes in IL-1β/IL-10 ratios by PBMo in ASD subjects [95].

  • In recent studies, we also found changes in miRNA in sera of ASD subjects, when tested by high-throughput deep sequencing. Again, changes in serum miRNA levels are closely associated with changes in IL-1β/IL-10 ratios by PBMo, production of monocyte cytokines (TNF-β, IL-6, IL-10, CCL2 mostly), along with parameters of mitochondrial respiration (manuscript submitted for publication). Interestingly, in ASD subjects, miRNA levels are mostly decreased, as compared to non-ASD controls (submitted for publication). Targeted genes by miRNAs that are altered in serum levels in ASD subjects with high or low IL-1β/IL-10 ratios are associated with pathways involved in innate immune responses, including the mTOR signaling pathway (unpublished observation).

The above-described findings may be best explained by altered innate immune responses associated with innate immune memory (trained immunity vs. tolerance). So, if this is the case, for these ASD subjects, can clinical features that indicate an alternation of innate immune memory be detected? The author is a pediatric immunologist and, as indicated before, as stated previously, observes exacerbation of neuropsychiatric symptoms, following immune insults. Herein, a representative ASD case, in which trained immunity may be associated with the onset and progression of ASD, is presented.

3.5 Case presentation

A 10-year-old female child presented to the pediatric allergy/immunology clinic at our institution secondary to fluctuating behavioral symptoms. Fluctuation of behavioral symptoms often occurred, following microbial infection.

The patient was born at 41 weeks of gestation via cesarean section due to breech presentation, following an uneventful pregnancy. The patient was developing typically until 24 months of age and then suffered from significant developmental regression. Prior to the onset of the developmental regression, parents took the patient to South Asia to visit other family members and friends. During this visit, the patient suffered an insect bite which was complicated by a secondary bacterial skin infection. When treated with oral antibiotics abroad, the patient developed generalized hives and severe GI symptoms (nausea, vomiting, diarrhea, and bloating): the patient then became intolerant to multiple foods. After returning to the United States, the patient was given multiple vaccinations including live vaccines to catch up the vaccination schedule. All these vaccines were given while the patient was still suffering from GI symptoms and an active skin infection. Within several days after vaccinations (multiple vaccines given all together), noticeable loss of cognitive and motor skills became apparent in the patient. The patient was eventually diagnosed with ASD around 2.5 years of age.

Eventually, the patient’s GI symptoms subsided, but this subject never regained the cognitive skills that this patient had once acquired prior to the onset of developmental regression. Prior to advancing to pre-kindergarten, the patient was given booster doses of vaccines which were well tolerated. However, after starting pre-kindergarten, the patient started getting sick frequently with upper respiratory infections, which often evolved into ear infection. The patient missed many days of school, since the patient suffered a prolonged course of illness and more severe symptoms, as compared to peers. While the patient presented with symptoms of upper respiratory infection, this patient’s behavioral symptoms continue to fluctuate, most evident in worsening of obsessive compulsive behaviors and frequency of “rage” episodes. Worsening behavioral symptoms would always follow immune insults, worse in a convalescence stage. Avoidance of sick contacts by placing the patient in home schooling attenuated the fluctuating behavioral symptoms. At 7–8 years of age, the fluctuating behavioral symptoms seen were mainly associated with teething. After the completion of teething, behavioral symptoms became more stable. However, the patient stopped growing, falling under the first percentile of the growth curve in height and weight. An exhausting workup for primary mitochondrial diseases, endocrine diseases, primary immunodeficiency with known gene mutations, and congenital metabolic and genetic diseases was unrevealing. However, video electric encephalogram revealed a focal epileptic activity. Family history is negative for neuropsychiatric, genetic, autoimmune, immune, and metabolic diseases.

In the case presented above, did neuroinflammation caused by maladapted trained immunity have a role in her clinical features? It is hard to prove, but it may be speculated that the initial stressful events that occurred abroad shaped trained immunity in this patient, and the subsequent multiple unrelated immune stimuli may have caused prolonged maladapted trained immunity, leading to persistent neuroinflammation and impairment of cognitive activity, as observed in the MIA models of ASD. Interestingly, changes in GI conditions, such as changes in microbiome, have been implicated with neuropsychiatric diseases, triggering maladapted trained immunity [96]. It is also reported that trained innate immunity can be induced in human monocytes by cow’s milk [97]. Thus her severe GI symptoms and subsequent intolerance to multiple foods may be associated with excessive trained immunity in the gut of this patient.

3.6 Evidence of impaired trained immunity

As summarized in the previous section, we have found that IL-1β/IL-10 ratios produced by PBMo are altered in some ASD subjects in association with fluctuating behavioral symptoms [94]. Thus if innate immune memory (trained immunity) is associated with her above-described remarkable clinical symptoms, we may also find altered IL-1β/IL-10 ratios, as an indicator of altered innate immune responses.

Thus we assessed IL-1β/IL-10 ratios produced by PBMo in response to a panel of innate immune stimuli, including β-glucan, as reported previously [95]. As shown in Figure 1, the presented case revealed increase in IL-1β/IL-10 ratios in response to zymosan, CL097, and β-glucan. High IL-1β/IL-10 ratio in response to CL097, an agonist of TLR7/TLR8, was especially striking. We also observed increase in production of TNF-α and IL-6 and decrease in the production of IL-10, as well. Given these findings, it is possible that maladapted trained immunity may have caused excessive inflammatory responses to various innate immune stimuli, which then led to developmental regression and fluctuating behavioral symptoms in this presented case.

Figure 1.

IL-1β/IL-10 ratios produced by purified peripheral blood monocytes in response to medium only (no stimulus), LPS (TLR4 agonist), zymosan (TLR2/TLR6 agonist), CL097 (TLR7/TLR8 agonist), and β-glucan in the presented case (patient) and control cells from a non-ASD neurotypical subject. IL-1β/IL-10 ratios are shown in a log scale.

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4. Conclusions

Our deepening knowledge of innate immune memory (trained immunity vs. tolerance) has shed light on the understanding of nonspecific effects of microbial infection and other immune stimuli, which have been implicated in the onset and progress of various neuropsychiatric diseases. Recent research indicates a possibility for a role of maladapted innate immune memory in various neuropsychiatric conditions. The finding of innate immune memory is especially exciting in the field of neuroimmunology, since we now likely have better tools for addressing the long-suspected role of immune-mediated inflammation that is not associated with specific pathogens or environmental factors, in various neuropsychiatric conditions. The concept of innate immune memory will be especially important in addressing insults to the brain during the early years of CNS development, and the resultant lasting intellectual disabilities, as seen in MIA models [70]. More importantly, an improved understanding of the role of innate immune memory (trained immunity vs. tolerance) in pathogenic neuroinflammation can lead to novel therapeutic measures that are desperately needed for the treatment of neuropsychiatric diseases.

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Acknowledgments

The part of the study presented in this manuscript was funded from the Jonty Foundation, St. Paul, MN. The author is thankful for the critical review of this manuscript by Dr. L. Huguenin.

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Conflict of interest

The author has nothing to declare.

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Abbreviations

Abantibody
Agantigen
APCAg-presenting cells
ApoEapolipoprotein E
ASDautism spectrum disorders
BCGBacillus Calmette-Guérin
Brg1brahma-regulated gene 1
BMDMcell, bone marrow-derived microglial cell
CAPScryopyrin-associated periodic syndrome
CARScompensatory anti-inflammatory response syndrome
CNScentral nervous system
DAMPsdamage-associated molecular patterns
EAEexperimental autoimmune encephalitis
GIgastrointestinal
HIF-1αhypoxia inducible factor-1α
IFNinterferon
ILinterleukin
IPLsimmune gene-priming lncRNAs
lncRNAslong noncoding RNAs
IRAKinterleukin-1 receptor-associated kinase
LPSlipopolysaccharide
MIAmaternal immune activation
MSmultiple sclerosis
MyD88myeloid differentiation factor 88
mTORmammalian target of rapamycin
NF-κBnuclear factor of κ chain of B cells
NKnatural killer
OxLDLoxidized low-density lipoprotein
OXPHOSoxidative phosphorylation
PAMPspathogen-associated molecular patterns
PBMCsperipheral blood mononuclear cells
PBMoperipheral blood monocytes
SHIP1SH2 domain-containing inositol phosphatase 1
SPUHSaint Peter’s University Hospital
TCAtricarboxylic acid
TLRToll-like receptor
TNFtumor necrosis factor
TREM-2triggering receptor expressed on myeloid cells 2
TRIFTIR-domain-containing adaptor-inducing interferon-ß
TSCtuberous sclerosis complex
UMLILOupstream master lncRNAs of the inflammatory chemokine locus

References

  1. 1. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews. Immunology. 2007;7(2):161-167
  2. 2. Salam AP, Borsini A, Zunszain PA. Trained innate immunity: A salient factor in the pathogenesis of neuroimmune psychiatric disorders. Molecular Psychiatry. 2018;23(2):170-176
  3. 3. van der Heijden C, Noz MP, Joosten LAB, Netea MG, Riksen NP, Keating ST. Epigenetics and trained immunity. Antioxidants & Redox Signaling. 2018;29(11):1023-1040
  4. 4. Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556(7701):332-338
  5. 5. Krakauer T. Inflammasomes, autophagy, and cell death: The trinity of innate host Defense against intracellular Bacteria. Mediators of Inflammation. 2019;2019:2471215
  6. 6. Peng Y, van Wersch R, Zhang Y. Convergent and divergent signaling in PAMP-triggered immunity and effector-triggered immunity. Molecular Plant-Microbe Interactions. 2018;31(4):403-409
  7. 7. McCoy KD, Ronchi F, Geuking MB. Host-microbiota interactions and adaptive immunity. Immunological Reviews. 2017;279(1):63-69
  8. 8. Farber DL, Netea MG, Radbruch A, Rajewsky K, Zinkernagel RM. Immunological memory: Lessons from the past and a look to the future. Nature Reviews. Immunology. 2016;16(2):124-128
  9. 9. Sfera A, Gradini R, Cummings M, Diaz E, Price AI, Osorio C. Rusty microglia: Trainers of innate immunity in Alzheimer’s disease. Frontiers in Neurology. 2018;9:1062
  10. 10. Sohrabi Y, Lagache SMM, Schnack L, Godfrey R, Kahles F, Bruemmer D, et al. mTOR-dependent oxidative stress regulates oxLDL-induced trained innate immunity in human monocytes. Frontiers in Immunology. 2018;9:3155
  11. 11. Benn CS, Netea MG, Selin LK, Aaby P. A small jab—A big effect: Nonspecific immunomodulation by vaccines. Trends in Immunology. 2013;34(9):431-439
  12. 12. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: Beneficial nonspecific effects in the neonatal period? The Journal of Infectious Diseases. 2011;204(2):245-252
  13. 13. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(43):17537-17542
  14. 14. Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature. 2009;457(7229):557-561
  15. 15. Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, et al. Modulation of Myelopoiesis progenitors is an integral component of trained immunity. Cell. 2018;172(1-2):147-161 e12
  16. 16. Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonca LE, Pacis A, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172(1-2):176-190 e19
  17. 17. Suliman S, Geldenhuys H, Johnson JL, Hughes JE, Smit E, Murphy M, et al. Bacillus Calmette-Guerin (BCG) revaccination of adults with latent mycobacterium tuberculosis infection induces long-lived BCG-reactive NK cell responses. Journal of Immunology. 2016;197(4):1100-1110
  18. 18. Jensen KJ, Larsen N, Biering-Sorensen S, Andersen A, Eriksen HB, Monteiro I, et al. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: A randomized-controlled trial. The Journal of Infectious Diseases. 2015;211(6):956-967
  19. 19. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: A program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098
  20. 20. Reimer-Michalski EM, Conrath U. Innate immune memory in plants. Seminars in Immunology. 2016;28(4):319-327
  21. 21. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345(6204):1250684
  22. 22. Ryskalin L, Limanaqi F, Frati A, Busceti CL, Fornai F. mTOR-related brain dysfunctions in neuropsychiatric disorders. International Journal of Molecular Sciences. 2018;19(8):1-29
  23. 23. Arts RJ, Joosten LA, Netea MG. Immunometabolic circuits in trained immunity. Seminars in Immunology. 2016;28(5):425-430
  24. 24. Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metabolism. 2016;24(6):807-819
  25. 25. Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204):1251086
  26. 26. Novakovic B, Habibi E, Wang SY, Arts RJW, Davar R, Megchelenbrink W, et al. Beta-glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell. 2016;167(5):1354-1368 e14
  27. 27. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Current Opinion in Chemical Biology. 2016;30:52-60
  28. 28. Shin Y, Chang YC, Lee DSW, Berry J, Sanders DW, Ronceray P, et al. Liquid nuclear condensates mechanically sense and restructure the genome. Cell. 2018;175(6):1481-1491 e13
  29. 29. Cho WK, Spille JH, Hecht M, Lee C, Li C, Grube V, et al. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science. 2018;361(6400):412-415
  30. 30. Fok ET, Davignon L, Fanucchi S, Mhlanga MM. The lncRNA connection between cellular metabolism and epigenetics in trained immunity. Frontiers in Immunology. 2018;9:3184
  31. 31. Fanucchi S, Fok ET, Dalla E, Shibayama Y, Borner K, Chang EY, et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nature Genetics. 2019;51(1):138-150
  32. 32. Nissen TN, Birk NM, Blok BA, Arts RJW, Andersen A, Kjaergaard J, et al. Bacillus Calmette-Guerin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial. European Journal of Clinical Microbiology & Infectious Diseases. 2018;37(1):29-41
  33. 33. Ifrim DC, Quintin J, Joosten LA, Jacobs C, Jansen T, Jacobs L, et al. Trained immunity or tolerance: Opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clinical and Vaccine Immunology. 2014;21(4):534-545
  34. 34. Butkeviciute E, Jones CE, Smith SG. Heterologous effects of infant BCG vaccination: Potential mechanisms of immunity. Future Microbiology. 2018;13:1193-1208
  35. 35. Netea MG, van der Meer JW. Trained immunity: An ancient way of remembering. Cell Host & Microbe. 2017;21(3):297-300
  36. 36. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Jacobs C, Xavier RJ, et al. BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. Clinical Immunology. 2014;155(2):213-219
  37. 37. Ifrim DC, Quintin J, Meerstein-Kessel L, Plantinga TS, Joosten LA, van der Meer JW, et al. Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis. Clinical and Experimental Immunology. 2015;181(3):434-440
  38. 38. Moorlag S, Roring RJ, Joosten LAB, Netea MG. The role of the interleukin-1 family in trained immunity. Immunological Reviews. 2018;281(1):28-39
  39. 39. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496(7444):238-242
  40. 40. Zhang W, Petrovic JM, Callaghan D, Jones A, Cui H, Howlett C, et al. Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures. Journal of Neuroimmunology. 2006;174(1-2):63-73
  41. 41. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L. IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. The FASEB Journal. 2003;17(14):2115-2117
  42. 42. Keddie S, Parker T, Lachmann HJ, Ginsberg L. Cryopyrin-associated periodic fever syndrome and the nervous system. Current Treatment Options in Neurology. 2018;20(10):43
  43. 43. O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nature Reviews. Immunology. 2016;16(9):553-565
  44. 44. Van den Bossche J, Baardman J, de Winther MP. Metabolic characterization of polarized M1 and M2 bone marrow-derived macrophages using real-time extracellular flux analysis. Journal of Visualized Experiments. 2015;(105):53424
  45. 45. Vergadi E, Vaporidi K, Tsatsanis C. Regulation of endotoxin tolerance and compensatory anti-inflammatory response syndrome by non-coding RNAs. Frontiers in Immunology. 2018;9:2705
  46. 46. Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). Journal of Neuroimmunology. 2009;206(1-2):121-124
  47. 47. Seeley JJ, Baker RG, Mohamed G, Bruns T, Hayden MS, Deshmukh SD, et al. Induction of innate immune memory via microRNA targeting of chromatin remodelling factors. Nature. 2018;559(7712):114-119
  48. 48. del Fresno C, Garcia-Rio F, Gomez-Pina V, Soares-Schanoski A, Fernandez-Ruiz I, Jurado T, et al. Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: Demonstration in isolated monocytes from cystic fibrosis patients. Journal of Immunology. 2009;182(10):6494-6507
  49. 49. Nahid MA, Satoh M, Chan EK. MicroRNA in TLR signaling and endotoxin tolerance. Cellular & Molecular Immunology. 2011;8(5):388-403
  50. 50. Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clinics in Chest Medicine. 2008;29(4):617-625, viii
  51. 51. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: New mechanisms, molecules and clinical significance. Trends in Immunology. 2009;30(10):475-487
  52. 52. Doxaki C, Kampranis SC, Eliopoulos AG, Spilianakis C, Tsatsanis C. Coordinated regulation of miR-155 and miR-146a genes during induction of endotoxin tolerance in macrophages. Journal of Immunology. 2015;195(12):5750-5761
  53. 53. Vergadi E, Vaporidi K, Theodorakis EE, Doxaki C, Lagoudaki E, Ieronymaki E, et al. Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice. Journal of Immunology. 2014;192(1):394-406
  54. 54. O’Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(17):7113-7118
  55. 55. Sun X, Sun J, Shao X, Feng J, Yan J, Qin Y. Inhibition of microRNA-155 modulates endotoxin tolerance by upregulating suppressor of cytokine signaling 1 in microglia. Experimental and Therapeutic Medicine. 2018;15(6):4709-4716
  56. 56. Magistri M, Faghihi MA, St Laurent G 3rd, Wahlestedt C. Regulation of chromatin structure by long noncoding RNAs: Focus on natural antisense transcripts. Trends in Genetics. 2012;28(8):389-396
  57. 57. Ulitsky I, Bartel DP. lincRNAs: Genomics, evolution, and mechanisms. Cell. 2013;154(1):26-46
  58. 58. Murphy MB, Medvedev AE. Long noncoding RNAs as regulators of toll-like receptor signaling and innate immunity. Journal of Leukocyte Biology. 2016;99(6):839-850
  59. 59. Du M, Yuan L, Tan X, Huang D, Wang X, Zheng Z, et al. The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation. Nature Communications. 2017;8(1):2049
  60. 60. Mia S, Warnecke A, Zhang XM, Malmstrom V, Harris RA. An optimized protocol for human M2 macrophages using M-CSF and IL-4/IL-10/TGF-beta yields a dominant immunosuppressive phenotype. Scandinavian Journal of Immunology. 2014;79(5):305-314
  61. 61. Chen J, Ivashkiv LB. IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(45):19438-19443
  62. 62. Shi L, Song L, Maurer K, Sharp J, Zhang Z, Sullivan KE. Endotoxin tolerance in monocytes can be mitigated by alpha2-interferon. Journal of Leukocyte Biology. 2015;98(4):651-659
  63. 63. Zhan X, Stamova B, Sharp FR. Lipopolysaccharide associates with amyloid plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review. Frontiers in Aging Neuroscience. 2018;10:42
  64. 64. Wlodarczyk A, Cedile O, Jensen KN, Jasson A, Mony JT, Khorooshi R, et al. Pathologic and protective roles for microglial subsets and bone marrow- and blood-derived myeloid cells in central nervous system inflammation. Frontiers in Immunology. 2015;6:463
  65. 65. Ataka K, Asakawa A, Nagaishi K, Kaimoto K, Sawada A, Hayakawa Y, et al. Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice. PLoS One. 2013;8(11):e81744
  66. 66. Greenhalgh AD, Zarruk JG, Healy LM, Baskar Jesudasan SJ, Jhelum P, Salmon CK, et al. Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury. PLoS Biology. 2018;16(10):e2005264
  67. 67. Tchessalova D, Posillico CK, Tronson NC. Neuroimmune activation drives multiple brain states. Frontiers in Systems Neuroscience. 2018;12:39
  68. 68. Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD. Microglia and memory: Modulation by early-life infection. The Journal of Neuroscience. 2011;31(43):15511-15521
  69. 69. Cao M, Cortes M, Moore CS, Leong SY, Durosier LD, Burns P, et al. Fetal microglial phenotype in vitro carries memory of prior in vivo exposure to inflammation. Frontiers in Cellular Neuroscience. 2015;9:294
  70. 70. Careaga M, Murai T, Bauman MD. Maternal immune activation and autism Spectrum disorder: From rodents to nonhuman and human primates. Biological Psychiatry. 2017;81(5):391-401
  71. 71. Rose DR, Careaga M, Van de Water J, McAllister K, Bauman MD, Ashwood P. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain, Behavior, and Immunity. 2017;63:60-70
  72. 72. Fu R, Shen Q , Xu P, Luo JJ, Tang Y. Phagocytosis of microglia in the central nervous system diseases. Molecular Neurobiology. 2014;49(3):1422-1434
  73. 73. Neher JJ, Neniskyte U, Brown GC. Primary phagocytosis of neurons by inflamed microglia: Potential roles in neurodegeneration. Frontiers in Pharmacology. 2012;3:27
  74. 74. Painter MM, Atagi Y, Liu CC, Rademakers R, Xu H, Fryer JD, et al. TREM2 in CNS homeostasis and neurodegenerative disease. Molecular Neurodegeneration. 2015;10:43
  75. 75. Ohrfelt A, Axelsson M, Malmestrom C, Novakova L, Heslegrave A, Blennow K, et al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Multiple Sclerosis. 2016;22(12):1587-1595
  76. 76. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Molecular Biology of the Cell. 2009;20(7):1981-1991
  77. 77. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Molecular Biology of the Cell. 2009;20(7):1992-2003
  78. 78. Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cellular Signalling. 2014;26(12):2694-2701
  79. 79. Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiology of Disease. 2008;32(3):329-339
  80. 80. Giorgi FS, Biagioni F, Lenzi P, Frati A, Fornai F. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. Journal of Neural Transmission (Vienna). 2015;122(6):849-862
  81. 81. Tramutola A, Triplett JC, Di Domenico F, Niedowicz DM, Murphy MP, Coccia R, et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): Analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. Journal of Neurochemistry. 2015;133(5):739-749
  82. 82. Ryskalin L, Lazzeri G, Flaibani M, Biagioni F, Gambardella S, Frati A, et al. mTOR-dependent cell proliferation in the brain. BioMed Research International. 2017;2017:7082696
  83. 83. Cleary C, Linde JA, Hiscock KM, Hadas I, Belmaker RH, Agam G, et al. Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders. Brain Research Bulletin. 2008;76(5):469-473
  84. 84. Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O, Ikeda K, et al. Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nature Communications. 2012;3:1292
  85. 85. Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83(5):1131-1143
  86. 86. Kara NZ, Flaisher-Grinberg S, Anderson GW, Agam G, Einat H. Mood-stabilizing effects of rapamycin and its analog temsirolimus: Relevance to autophagy. Behavioural Pharmacology. 2018;29(4):379-384
  87. 87. Jyonouchi H, Geng L, Streck DL, Toruner GA. Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes. Journal of Neuroimmunology. 2011;238(1-2):73-80
  88. 88. Jyonouchi H, Geng L, Davidow AL. Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: An inflammatory subtype? Journal of Neuroinflammation. 2014;11:187
  89. 89. Turner TN, Eichler EE. The role of De novo noncoding regulatory mutations in neurodevelopmental disorders. Trends in Neurosciences. 2019;42(2):115-127
  90. 90. Cristiano C, Lama A, Lembo F, Mollica MP, Calignano A, Mattace RG. Interplay between peripheral and central inflammation in autism Spectrum disorders: Possible nutritional and therapeutic strategies. Frontiers in Physiology. 2018;9:184
  91. 91. Jiang NM, Cowan M, Moonah SN, Petri WA Jr. The impact of systemic inflammation on neurodevelopment. Trends in Molecular Medicine. 2018;24(9):794-804
  92. 92. Siniscalco D, Schultz S, Brigida AL, Antonucci N. Inflammation and neuro-immune dysregulations in autism spectrum disorders. Pharmaceuticals (Basel). 4 June 2018;11(2):56
  93. 93. Jyonouchi H, Geng L, Streck DL, Dermody JJ, Toruner GA. MicroRNA expression changes in association with changes in interleukin-1ss/interleukin10 ratios produced by monocytes in autism spectrum disorders: Their association with neuropsychiatric symptoms and comorbid conditions (observational study). Journal of Neuroinflammation. 2017;14(1):229
  94. 94. Jyonouchi H, Geng L, Buyske S. Interleukin-1β/Interleukin10 ratio produced by monocytes as a biomarker of neuroinflammation in autism. Journal of Clinical & Cellular Immunology. 2017;8(3):1000503
  95. 95. Jyonouchi H, Geng L, Rose S, Bennuri SC, Frye RE. Variations in mitochondrial respiration differ in IL-1ß/IL-10 ratio based subgroups in autism spectrum disorders. Frontiers in Psychiatry. 2019;10(Feburary):1-15
  96. 96. Rudzki L, Szulc A. “Immune gate” of psychopathology-the role of gut derived immune activation in major psychiatric disorders. Frontiers in Psychiatry. 2018;9:205
  97. 97. van Splunter M, van Osch TLJ, Brugman S, Savelkoul HFJ, Joosten LAB, Netea MG, et al. Induction of trained innate immunity in human monocytes by bovine milk and milk-derived immunoglobulin G. Nutrients. 27 Sept 2018;10(10)

Written By

Harumi Jyonouchi

Submitted: December 10th, 2018 Reviewed: May 31st, 2019 Published: July 4th, 2019