Generation of SAA fragments.
Abstract
Serum amyloid A1 (SAA1), a major isoform of acute-phase SAA, is a well-known precursor of amyloid A (AA) that contributes to secondary amyloidosis with its tissue deposition. Acute-phase SAA is also a biomarker of inflammation. Recent studies have focused on the roles for acute-phase SAA in the regulation of immunity and inflammation. In vitro characterization of recombinant human SAA identified its chemotactic and cytokine-like properties, whereas the use of SAA isoform-specific transgenic and knockout mice has led to the discovery of new functions of SAA proteins in host defense and tissue homeostasis. Characterization of SAA-derived peptides has shown that fragments of SAA, generated through proteolysis, are bioactive and may contribute to a growing list of functions related to inflammation. This chapter summarizes recent progress in the studies of acute-phase SAA and its fragments in inflammation and immunomodulation.
Keywords
- SAA
- inflammation
- immunity
1. Introduction
Serum amyloid A (SAA) was identified in early studies as the precursor of amyloid A (AA), the tissue deposit of which causes secondary amyloidosis [1, 2, 3, 4]. SAA was also found as one of the major acute-phase proteins that are produced in large quantities by hepatocytes and released to blood circulation in response to trauma, infection, late-stage malignancy and severe stress [5, 6]. Extending from these early findings, increased levels of SAA were found both in plasma and in injured and inflammatory tissues. A large body of literature reports SAA as a biomarker in a variety of diseases ranging from acute inflammation, chronic inflammation, type-2 diabetes, malignancy and postsurgical complications [7, 8, 9]. However, the biological functions of SAA remained largely unknown for many years [10] despite efforts in it biochemical characterization, gene cloning of its isoforms, studies of the interactions between SAA and high-density lipoprotein (HDL), and delineation of its regulatory activities in inflammation and immunity. The widespread use of recombinant human SAA proteins has accelerated the characterization of the biological functions of SAA
2. SAA and its role in amyloidosis
SAA is the general name of a family of proteins with high sequence homology but encoded by distinct genes [16]. Both humans and mice have 4 SAA genes, but in human the
At the primary sequence level, the human and mouse SAA proteins share high sequence homology (Figure 1), suggesting that these proteins may have similar functions although their modes of expression vary. Of note, although mouse SAA3 has an expression profile different from that of SAA1 and SAA2, its sequence is as homologous to human SAA1 as mouse SAA1 and SAA2 (Figure 1). The sequence homology suggests that the functions of SAA3, expressed upon induction by inflammatory cues in various mouse tissues, may be similar to those of human SAA1 and SAA2.
Human SAA1 has been widely studied for its functions. SAA1 was first identified as a serum component recognized by antibodies raised against the amyloid fibril protein known as amyloid A (AA). In one of the studies, antisera were prepared against the major nonimmunoglobulin component of secondary amyloidosis. The antisera were able to detect a serum component that was present at much higher levels in more than half of the pathological samples collected from patients compared to only 7% of normal controls [1]. Husby and Natvig found that the serum component detected by the antisera against AA was larger and its circulation level was increased with age and during pregnancy [2]. The protein immuoprecipitated by the antisera was of low molecular weight with similar but not identical amino acid composition of the AA fibrils [22]. It was thought that AA could be a subunit of the SAA protein [22], which was identified as a cleavage product of SAA.
Amyloidosis develops when insoluble amyloid fibrils accumulate in the extracellular space of the tissues and organs in the body. Patients with chronic inflammatory diseases may develop AA amyloidosis, also termed secondary amyloidosis [23, 24]. SAA as an amyloid protein has the propensity of fibril formation. However, how SAA forms fibril is not fully understood. A number of observations suggest that SAA produced in inflammatory tissues is endocytosed into macrophages [25], where the acidic environment of lysosome promotes fibril formation [26]. The small amount of fibril formed is then exocytosed to the cell surface, prompting a nucleation-dependent incorporation of additional SAA into fibrils [27]. More recent studies have shown that SAA forms stable oligomers at pH of 3.5–4.5, that are resistant to proteolysis and undergo α-helix to β-sheet conversion. The SAA accumulated in lysosomes eventually escape from the cells [28]. Based on these studies, AA fibril formation is a biphasic process [27, 29] that involves an intracellular phase and an extracellular phase. Proteolysis is involved probably in both phases [27, 30]. In the second phase, additional SAA proteins may be recruited with nucleation of AA fibrils, and cleavage of SAA may be a post-fibrillogenic event [31].
Recent delineation of the crystal structure of human SAA1 provides a structural basis for AA amyloidosis [32]. Despite high levels of sequence homology, different SAA isoforms have different propensity in forming AA fibrils. Human SAA1.1 has a high tendency of amyloidogenicity, whereas SAA2.2 found in the CE/J mice did not form amyloid fibrils [33, 34] despite sequence homology as high as 94% with SAA1.1. It was found that the structural determinants for amyloidogenicity reside in the first 10–15 residues of mature SAA protein [35]. In a more recent study, SAA2.2 was found to form small fibrils within a few hours, in contrast to the long lag time of SAA1.1 that was characteristically oligomer-rich [36]. These fibrils exhibited different morphology and the fibrils of SAA1.1 were found to be pathogenic. The results of this study suggest that fibrillation kinetics and prefibrillar oligomers of different SAA isoforms may determine their pathogenicity even though they all possess intrinsic amyloidogenicity.
3. Production and characterization of SAA fragments
In AA amyloidosis, the insoluble AA amyloid protein is derived from the proteolytic cleavage of SAA, generating an N-terminal fragment of SAA. In some cases, this AA amyloid protein lacks amino acids at both N- and C-terminus compared to the full-length SAA. One reported study found that the AA fibril protein purified from rheumatoid arthritis patients with secondary amyloidosis contained 2 fragments with residues 1–50 and 1–45 [37]. However, a SAA fragment with residues 1–76 (or 2–76) was most commonly found in amyloid fibrils, such as those from the livers and spleens of patients with familial Mediterranean fever (FMF), tuberculosis, Hodgkin’s diseases and bronchiectasis [24, 38].
In patients with rheumatoid arthritis, higher serum levels of metalloproteinases (MMPs)-1, -2, -3 and -9 were detected compared to healthy controls [39, 40], and the production of these enzymes could be stimulated by SAA [41, 42]. Besides, these MMPs were shown to cleave SAA and AA amyloid protein
In addition to their roles in AA amyloidosis, SAA-derived fragments may have other biological functions. A recent study demonstrated that MMP-9 could rapidly cleave human SAA1 within 30 minutes
Accumulating evidence suggests that some of the observed biological functions of SAA, other than those related to amyloidosis, may be attributed to SAA-derived fragments rather than the intact protein. In some of these studies, synthetic peptides based on SAA protein sequence were prepared to verify or identify the potential functions. SAA-derived peptides with IFNγ-inducing capability were found in human rheumatic synovial fluid [51]. An SAA2-derived peptide with chemotactic activity for B lymphocytes was found in cow milk [52]. In a recent study, a fragment of SAA1 (46–112) was found in bovine serum and is equivalent to human SAA1 (47–104). The synthetic peptides of this fragment failed to directly induce chemotaxis and chemokine production (CXCL8 and CCL3) in human neutrophils and monocytes, but it synergized with CXCL8 or CCL3 to induce chemotaxis via FPR2 [47]. Studies were also conducted to examine potential functions of SAA and its peptides in LPS-induced inflammatory response. SAA-derived fragments lacking both N- and C-terminal residues were expressed as recombinant proteins and texted for their activities
4. The cytokine-like activities of recombinant SAA
Recombinant SAA was used in an early study that identified the SAA protein as a chemoattractant for phagocytes [54]. Xu et al. reported that SAA also induced the migration and adhesion of lymphocytes [55]. These studies were among the first to identify leukocyte-activating activities of the recombinant SAA protein. SAA differs from chemokines as it lacks the characteristic cysteine residues that form disulfide bonds for structural stabilization. It was not until 2014 when the crystal structures of two SAA proteins were solved [32, 56]. The 4-helix bundle structure of the SAA monomers and the propensity of forming multimers [32, 56] are strikingly different from the known structural properties of chemokines [57].
Studies conducted by Patel et al. [58] and Fulaneto et al. [59] revealed cytokine-like activities of SAA for its induction of IL-1β, TNFα, IL-1RA and IL-8. Of note, the study conducted by Patel and coworkers used both the recombinant human SAA (rhSAA) and purified SAA-HDL complex, although they found that the cytokine-inducing activity of the SAA-HDL complex was much lower than that of rhSAA. These studies were followed by reports that SAA in neutrophils could induce IL-8 expression through one of the chemoattractant receptors [60] that also mediates anti-inflammatory activities when stimulated by the eicosanoid lipoxin A4 [61, 62]. In addition to proinflammatory cytokines, rhSAA was found to stimulate monocyte expression of tissue factor [63]. Injection of rhSAA to mice increased G-CSF production and neutrophil expansion [64]. SAA also induced the expression of immunomodulatory cytokines including selective induction of IL-23 over IL-12 [65] and the induction of IL-33 expression [66]. The transcription factors NF-κB, IRF4 and IRF7 have been implicated in SAA-induced gene expression [66, 67]. In addition, SAA appears to be involved in epigenetic regulation of gene expression [68].
One of the cellular targets of SAA is macrophages, a major source of cytokines and most if not all SAA receptors. Macrophages may be differentiated into M1 or M2 phenotypes. Studies have shown that SAA may influence macrophage differentiation. Anthony et al. examined the effects of SAA
SAA has been identified as an endogenous activator of the NLRP3 inflammasome, which is critical to the process of pro-IL-1β. Niemi et al. reported that SAA provided a signal for pro-IL-1β expression and for inflammasome activation [70]. At least 3 SAA receptors, including TLR2, TLR4 and the ATP receptor P2X7, were involved. Interestingly, inflammasome activation was dependent on the activity of cathepsin B, the expression of which was induced by SAA. Therefore, SAA-induced secretion of cathepsin B could facilitate extracellular processing of SAA and development of AA amyloidosis. Ather et al. showed SAA3 expression in the lungs of mice exposed to mixed Th2/Th17-polarizing allergic sensitization regimens [71]. SAA instillation into the lungs elicited pulmonary neutrophilic inflammation and activation of the NLRP3 inflammasome, thereby promoting IL-1β secretion by dendritic cells and macrophages. SAA administered into the lungs also served as an adjuvant that sensitized mice to inhaled OVA, promoting IL-17 production from restimulated splenocytes and leukocyte influx. Collectively, these findings illustrate a stimulatory function of SAA in the induced expression of IL-1β.
5. SAA receptors
It has long been suspected that the diverse functions of SAA are mediated by cell surface receptors. Studies conducted in the past 20 years have led to the identification of several cell surface receptors for SAA in addition to a number of binding proteins (Figure 2). In 1999, Su et al. reported the involvement of formyl peptide receptor 2 (FPR2, also termed FPRL1 [72, 73]), in the chemotactic activity of SAA [74]. FPR2 is a G protein-coupled chemoattractant receptor initially identified as a homolog of human FPR1 with low-affinity binding of formylated peptide [75, 76, 77]. The identification of FPR2 as a receptor for SAA is consistent with reports that SAA induces migration of phagocytes and to a lesser extent, lymphocytes [54, 55]. Subsequent studies have shown that a number of biological functions of SAA, ranging from chemotaxis and superoxide generation to induced expression of proinflammatory cytokines and matrix metalloproteases, are mediated through FPR2 [47, 60, 78, 79, 80, 81, 82, 83, 84, 85].
The identification of cytokine-like activities of recombinant SAA protein suggests the involvement of receptors that typically mediate phagocyte cytokine production. The finding that SAA selectively induces IL-23 but not IL-12 expression suggests a pattern similar to that of Toll-like receptor (TLR)-mediated cytokine induction [65]. In 2008, two of the TLRs were identified as SAA receptors. TLR2, and more specifically the TLR2-TLR1 heterodimer, was found to mediate SAA-induced NF-κB activation leading to the expression of several proinflammatory cytokines and chemokines [86]. TLR2 is also responsible for SAA-induced neutrophil expansion through upregulation of G-CSF [64]. TLR4 was found to mediate SAA-induced expression of iNOS and activation of the related signaling pathways [87]. Despite differences in primary and high-level structures between SAA and the microbial ligands for these receptors, the two TLRs mediate SAA functions both in transfected cells expressing the receptors and
RAGE (receptor for advanced glycation end product) is a multiligand immunoglobulin superfamily cell surface molecule. In a study of AA amyloidosis, RAGE was identified as a receptor of SAA [93]. The expression of RAGE and its interaction with SAA coincide with cell stress, and RAGE has been shown to mediate the NF-κB activating effect of SAA [93, 94]. SAA also binds to soluble RAGE [63]. NF-κB activation induced by SAA interaction with RAGE apparently contributed to the expression of tissue factor in monocytes through MAP kinase activation. Inhibition of RAGE by a RAGE competitor, by soluble RAGE, and by anti-RAGE IgG reduced the SAA-stimulated tissue factor expression [63]. RAGE is also reported to mediate the proinflammatory activity of SAA in uremia-related atherosclerosis, based on a study using the
Scavenger receptors on macrophages play important roles in the removal of debris during tissue injury and in macrophage transport of lipids. The scavenge-receptor SR-BI has been known for mediating cholesterol efflux, in which SAA plays a role [96]. Two independent studies published in the same year reported the identification of SR-BI as an SAA receptor [97, 98]. Direct binding assays using radiolabeled SAA found its interaction with SR-B1 in cells that express this receptor [97]. SR-BI and its human homolog CLA-I mediate SAA uptake and its downstream signaling, including the activation of ERK and p38 MAPK that leads to IL-8 expression [98]. A more recent study reported that SR-BII, a splice variant of SR-BI, also serves as a SAA receptor for uptake and proinflammatory signaling through MAP kinase signaling [99].
The human P2X7 purinergic receptor is an ionotropic receptor found at high expression levels in immune cells such as macrophages and microglia. Activation of P2X7 receptor by extracellular ATP opens a cation channel, allowing K+ efflux that is associated with processing of pro-interleukin IL-1β and IL-18. Christenson et al. found that SAA, either recombinant or purified from the plasma of rheumatoid arthritis patients, could suppress apoptosis of human neutrophils, an effect abrogated by antagonizing the nucleotide receptor P2X7 [100]. Niemi et al. reported that the P2X7 receptor plays a role in SAA-mediated activation of NLRP3, thereby explaining the involvement of SAA in the processing of pro-IL-1β [70]. However, a recently published work indicates that in murine J774 and bone marrow-derived macrophages, SAA stimulates IL-1β secretion through a mechanism that depends on NLRP3 expression and caspase-1 activity but not the P2X7 receptor [101].
Collectively, published reports have identified several functional receptors that mediate SAA signaling. It is likely that these receptors and their downstream signaling pathways have substantial cross-talk that together contributes to the diverse immunomodulatory and homeostatic functions of SAA.
Recent studies have shown that recombinant human SAA, which has been widely used in in
6. Immunomodulatory functions of SAA in disease models
Since most of the early studies were conducted using cell lines and isolated primary cells such as monocytes and neutrophils, these experimental findings are now examined in an
Transgenic expression of human SAA1 in mice is another approach used in studies of the
SAA gene knockout mice were generate to examine the physiological functions of the individual SAA proteins. After observing SAA1 and SAA2 expression in intestinal epithelial cells and conforming their cell-protecting effect in epithelial cell line co-cultured with
A role for SAA as a mediator of local immune response has been reported recently. In a study of segmented filamentous bacteria (SFB) for its involvement in mucosal defenses and autoimmune diseases through RORγ+ Th17 cells, Sano et al. found that direct contact of SFB with epithelium in the ileum could induce SAA1 and SAA2 expression and promote local IL-17A expression in RORγ(+) T cells. The mechanisms involved an IL-23R/IL-22 circuit and the participation of type 3 innate lymphoid cells (ILC3) that secretes IL-22 [111]. Likewise, Atarashi et al. investigated a group of intestinal microbes for their ability to induce Th17 response, and found that SFB could stimulate intestinal epithelial cells to generate SAA and ROS, creating an amplification loop for sustained production of SAA by both epithelial cells and myeloid cells that led to local Th17 response [112]. These findings provide direct evidence for the contribution of epithelial SAA to intestinal homeostasis in an environment where host interaction with gut microbiota influences the health states of individuals.
In addition to studies of the
Several studies of the
Collectively, results from the studies of SAA proteins in mice identified important functions of SAA that were previous unknown from
7. Conclusion remarks
SAA has emerged from a precursor of AA to a modulator of immunity and inflammation. Several developments, including the ability to express recombinant SAA proteins, the generation of genetically altered mice expressing SAA transgenes or deletion of a specific SAA gene, and the availability of crystal structures of SAA proteins, have helped to advance our understanding of SAA for its functions in host defense, lipid metabolism, adipogenesis, and neuroprotection. In coming years, studies will likely focus on the comparison of SAA functions
Acknowledgments
This work was supported in part by grants from the Science and Technology Development Fund of Macau (026/2016/A1) and the University of Macau (MYRG2016-00152-ICMS-QRCM and CPG2015-00018-ICMS).
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