Open access peer-reviewed chapter

Cannabinoid Receptors as Regulators of Neutrophil Activity in Inflammatory Diseases

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Mariana Conceição Souza and Elaine Cruz Rosas

Submitted: May 16th, 2018 Reviewed: October 12th, 2018 Published: November 27th, 2018

DOI: 10.5772/intechopen.81995

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Abstract

Cannabinoids are compounds present in Cannabis sativa (phytocannabinoids), endogenously produced (endocannabinoids) or synthesized, that bind to G protein-coupled receptors named cannabinoid receptors B1 and B2. They were first described as psychotropic compounds; however, cannabinoids are also potent immunoregulatory agents. Cannabinoids can modulate neutrophil activity in sterile and infectious inflammatory diseases. Concerning sterile inflammatory diseases as arthritis, ischemic diseases, and colitis, the use of CB2 agonist impairs the intracellular signaling pathways involved in the production of inflammatory mediators and expression of adhesion molecules. As a consequence, neutrophils did not release metalloproteinases either to adhere to endothelial cells, resulting in reduced tissue damage. A similar anti-inflammatory CB2 agonist mechanism of action in sepsis and mycobacterial infection models is observed. However, it is not clear if inflammation resolution promoted by cannabinoid treatment during infection is also related to microbial viability. Despite the growing literature showing the effects of cannabinoids on neutrophils, there are still some gaps that should be filled before proposing cannabinoid-based drugs to treat neutrophil-dependent diseases.

Keywords

  • cannabinoid agonist
  • inflammation
  • infection
  • endocannabinoids
  • phytocannabinoids
  • synthetic cannabinoids

1. Introduction

Neutrophils have been classically recognized as the most relevant cell during acute inflammatory responses and, more recently, in chronic inflammation [1]. On the one hand, neutrophils produce bactericidal molecules and coordinate the accumulation of pro-resolving cells. On the other hand, neutrophil over activation leads to tissue damage. In this context, several approaches have been proposed to regulate the accumulation and the activity of neutrophils in pathological conditions.

In parallel, the findings concerning the importance of the endocannabinoid system as the endogenous immunoregulatory mechanism raise questions on how it could be therapeutically used to treat inflammatory diseases. In this chapter, we discuss how the endocannabinoid system can be used to modulate the activity of neutrophils in sterile and infectious inflammatory diseases.

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2. Cannabinoid system

Cannabis sativa(marijuana) is one of the oldest plants that produced psychoactive effects on humans. In addition, it has been used in medicine in controlling pain, convulsion, inflammation, and asthma [2, 3]. Cannabinoids are a group of lipophilic and pharmacologically active compounds present in C. sativa. The first component from cannabis identified was the tetrahydrocannabinol (Δ9-THC) and and, as other cannabinoids, binds to G protein-coupled receptors (GPCRs) named cannabinoid receptors [4, 5].

Cannabinoid receptor agonists are responsible for several biological effects, such as analgesic, antiemetic, antitumor, and anti-inflammatory [6, 7, 8, 9, 10, 11, 12, 13], and are classified into three groups based on their origin: endogenous cannabinoids (endocannabinoids—Figure 1a and b), phytocannabinoids (Figure 1c and d), and synthetic cannabinoids (Figure 1e and f) [5].

Figure 1.

Chemical structure of some representatives of the cannabinoid agonists. (a) 2-AG, (b) AEA, (c) cannabidiol, (d) β-caryophyllene, (e) JWH-133, and (f) WIN 55212-2.

Endocannabinoids (eCBs) are eicosanoids derived from polyunsaturated chain fatty acids, such as arachidonic acid, and comprise amides, esters, and ether [14]. Anandamide (AEA) was the first endocannabinoid described in the mammalian brain and other tissues [15], followed by 2-arachidonoylglycerol (2-AG) [16, 17]. The AEA and 2-AG represent the major substances of this class. The eCBs together with the cannabinoid receptors and the enzymes that regulate their biosynthesis and degradation constitute the “endocannabinoid system” [18]. Beyond the well-known psychotropic effects, the endocannabinoid system plays an essential immunomodulatory role by modulating the release of cytokines and on acute or chronical diseases through two main ways, neuro- and immunomodulation [19, 20].

The group of phytocannabinoids consists of active substances initially extracted from Cannabis sativa, whose pharmacological activity is associated with the terpene phenolic class. Phytocannabinoids are classified into two groups: psychoactive cannabinoids, such as Δ9-THC, and non-psychoactive such as cannabidiol and cannabinol [21, 22]. More recently, other molecules have been isolated from different plant species, which exert effects through cannabinoid receptors, such as the alkylamides derived from Echinacea angustifoliaand Otanthus maritimusand sesquiterpene, as β-caryophyllene, found in some plant species from Copaiferagenus [23, 24, 25, 26, 27].

The characterization of the chemical structure of Δ9-THC and endocannabinoids allowed the development of synthetic cannabinoids. From THC, it was possible to synthesize several compounds that have similar chemical structures with different levels of affinity for cannabinoid receptors [5, 28]. Synthetic cannabinoids have been used as a pharmacological tool for in vivoor in vitrostudies to explore the therapeutic potential of the cannabinoid system. However, it has already been described that metabolites form dipyrone and paracetamol exert its analgesic effects by inhibiting endocannabinoid biosynthesis and binding of cannabinoid receptors, respectively [29].

The cannabinoid receptors CB1 and CB2 are the main receptors of the cannabinoid system. Both belong to the family of GPCRs, specifically inhibitory G protein (Gi) [30]. The binding of agonists to cannabinoid receptors inhibits adenylate cyclase (AC) and modulates activation of different members of the MAPK family, including ERK1/ERK2, p38, and JNK1/2 (Figure 2) [30, 31, 32, 33, 34, 35, 36, 37]. By inhibiting AC, the reduction of the second messenger cyclic adenosine monophosphate (cAMP) leads to the opening of rectifying potassium channels. CB1 also mediates the inhibition of N-type and P/Q-type calcium currents [22, 38]. Besides CB1 and CB2, the existence of a third cannabinoid receptor (CB3) has been suggested [39], and there are two orphan G protein-coupled receptors (GPCRs) which overlap with CB1 and CB2, named GPR18 and GPR55 [40]. In addition to activation via GPCRs, cannabinoids can perform their actions by activating PPARs, including PPARγ [41, 42, 43].

Figure 2.

Neutrophil activated expresses cannabinoid receptors (CB receptors). The cannabinoid receptors CB1 and CB2 belong to the family of GPCRs, specifically inhibitory G protein (Gi/0). The binding of agonists to cannabinoid receptors inhibits the activation of different members of the MAPK family (ERK1/2, p38, and JNK1/2), gene expression, as well as reduces cyclic adenosine monophosphate (cAMP) levels by inhibiting adenylate cyclase (AC) activity.

CB1 is expressed in the central nervous system, especially by neurons [44] and modulates physiological processes, such as motor behavior, learning, memory and cognition, and pain perception [45]. This receptor is associated with the psychotropic effects of cannabinoid agonists, such as THC [46, 47].

CB2 is the peripheral receptor for cannabinoid agonists. It is mainly expressed in immune tissues such as the spleen and thymus as well as in blood cell subpopulations such as CD4 and CD8 lymphocytes, neutrophils, monocytes, natural killer (NK) cells, and B lymphocytes [47]. Nevertheless, CB2 is also found at low levels in neuronal and nonneuronal cells of the brain, but it does not produce psychoactive effects [47, 48, 49].

The CB2 expression intensity in immune cells depends on cell populations and activation state [50, 51]. Macrophages from different tissues increase CB2 expression after stimulation with interferon (IFN)-γ, which suggests that macrophages activated during an inflammatory process are more sensitive to the action of cannabinoid agonists than those in the resting state [52]. The first evidence that cannabinoids might modulate cytokine production was in the mid-1980s when murine cells treated with agonist cannabinoid reduced the levels of type I interferons (IFN-α and IFN-β) after stimulation with LPS or polyinosinic-polycytidylic acid (polyI:C). Many subsequent studies have shown that cannabinoids inhibited the production of cytokines in innate and adaptive immune responses, both in animal models and in human cell cultures (to review [53]). In such a way, CB2 has become an important target, especially in inflammatory conditions. The CB2 receptor modulates immune cell functions, both in vitroand in animal models of inflammatory diseases. In this context, some studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype (to review [19]). Besides, CB2 agonists have an inhibitory effect on leukocyte migration and in the production of pro-inflammatory mediators in vivoand in vitro, showing a high anti-inflammatory potential [54]. Due to the lack of psychotropic effects, CB2 agonists are considered a promising therapeutic strategy for the treatment of chronic inflammatory diseases. Preclinical studies showed the action of CB2 agonists on different experimental models of inflammation, such as colitis, arthritis, cerebral ischemia, and sepsis [10, 53, 55, 56, 57, 58, 59], and in these studies, they showed that the action of CB2 agonists modulated the neutrophil activity.

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3. Neutrophils, cannabinoid system, inflammation, and infection

3.1. Neutrophils and cannabinoid system

Neutrophils play a crucial role in inflammatory processes, which are present in the pathology of different diseases. The neutrophil recruitment to the inflammatory site is an essential stage in the inflammatory responses; these cells are released from the bone marrow to the periphery immediately after the first signal of inflammation. The mobilization of neutrophils from the bone marrow is conducted by the hematopoietic cytokine granulocyte colony-stimulating factor (G-CSF), which mobilizes neutrophils indirectly by shifting the balance between ligands to CXCR4 (CXCL12) and CXCR2 (CXCL1 and CXCL2) [60]. Neutrophil-active chemoattractant, as chemokines CXCL1 and CXCL2, is produced and released within the bone marrow and in inflamed tissue. In this context, chemokines from inflamed foci might make their way to the bone marrow and modulate neutrophil egress. Thus, CXCL1 and CXCL2 can act locally by inducing neutrophil recruitment from blood to peripheral tissue and systemically by inducing neutrophil mobilization from the bone marrow to the bloodstream [61].

Once in the peripheral blood, neutrophils can be rapidly recruited into inflamed or infected tissues. A panel of diverse stimuli, especially pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), activates macrophages, mast cells, or stromal cells to produce and release pro-inflammatory mediators as interleukin (IL)-1β, tumor necrosis factor (TNF), CXCL8, CXCL1, CXCL2, and lipid mediators, such as leukotriene B4 (LTB4) and endocannabinoids [61, 62]. In inflammatory loci, neutrophils find antigen, molecules, and/or immune complexes that trigger different actions, such as phagocytosis, production of reactive oxygen species (ROS), and release of enzyme-rich granules (as collagenases, gelatinases, neutrophil myeloperoxidase (MPO), and elastase [63]). Neutrophils enter the tissue through surface molecules which interact with vascular endothelial cells. This process is accompanied by a regulated rearrangement of the cytoskeleton of neutrophils that lead to actin polymerization [64], which is mainly governed by members of the Rho family GTPases including RhoA, Rac1, and Cdc42 [65].

Concerning cannabinoid receptor expression, it was observed that neutrophil from healthy donors expresses low levels of CB2 [66]. In addition, it was shown that the CB2 receptor plays a crucial role in neutrophil differentiation, and it has been implicated in the development of leukemia [67, 68].

The role of the cannabinoid system in neutrophil migration is controversial. The activation of CB2 receptors by 2-AG did not induce polarization and migration of human blood neutrophils [69]. However, pretreatment of neutrophils with 2-AG inhibited the fMLP- and CXCL8-induced migration without affecting the polarization of the cells [69]. In contrast, McHugh and coworkers showed that 2-AG does not inhibit the migration of human neutrophils toward fMLP and does not show chemotactic effects by itself [70]. Furthermore, Balenga and coworkers showed that 2-AG induces migration of neutrophils toward inflammatory sites, through cross talk with activated GPR55 [62].

Despite the uncertainty regarding the involvement of CB2 agonist with the neutrophil migration and action, some studies show that there is a relationship between neutrophils and cannabinoid system in the pathogenesis of inflammatory or infection diseases (Table 1). In the next section, we will discuss the cannabinoid system and its action on the neutrophil participation in inflammatory and infection conditions [54, 62, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85].

Table 1.

Cannabinoid agonists, which exert action on neutrophils.

3.2. Neutrophils, cannabinoid system, and inflammation

The action of CB2 agonists on their receptors impairs the secretion of pro-inflammatory cytokines and chemokines and reduces the recruitment of neutrophils. As discussed previously, neutrophils play a significant role in inflammatory diseases, including acute, chronic, autoimmune, infectious, and noninfectious conditions. The relation between neutrophil and cannabinoid system in inflammatory disease was discussed in this section.

Increased macro- and microscopic colon damage scores, a high number of macrophage and neutrophil and MPO activity, characterizes experimental colitis. The activation of CB receptors by their ligands produces a protective effect in experimental colitis by decreasing prostaglandin, ROS and nitric oxide production, and reduction of leukocyte accumulation as neutrophils, resulting in diminished of colon tissue inflammation. Besides, mice lacking functional CB receptors are less resistant to colon inflammation than wild-type animals [53, 86]. The synthetic non-psychotropic cannabinoids as JWH-133, cannabinoid from the plant as cannabigerol [87] and β-caryophyllene [54], and synthetic atypical cannabinoid O-1602 (non-CB1 and CB2 ligands) [88] have been able to inhibit neutrophil recruitment in colitis models. Thus, during inflammation, the CB2 receptor activation by endocannabinoids or synthetic cannabinoid provides a mechanism for the reestablishment of regular GI transit (to review [89]).

Neutrophils are also essential cells in the development of arthritis. Neutrophils are abundant in inflamed joints, and these cells are essential to the initiation and progression of rheumatoid arthritis (RA). Neutrophil effector mechanisms include the release of pro-inflammatory cytokines, reactive oxygen and nitrogen species (ROS and RNS), and granules containing derivative enzymes, which can cause further damage to the tissue and amplify the inflammatory response [90]. In such way, it has already been described that in RA there is an increase of CB2 expression and elevated endocannabinoid levels, observed in the synovial tissue and fluid from a patient with this disease [91]. Synovial fibroblasts and macrophages are mainly responsible for endocannabinoid production. These cells also are essential in the production of chemokines (CXCR1 or 2 ligands, such as CXCL8), the C5a fragment of the complement system, and LTB4 which are responsible for neutrophil mobilization to the synovial cavity [61]. In this context, the activation of CB2 receptors inhibits the production of pro-inflammatory mediators, like chemokines, which reduces the leukocyte migration, like neutrophils, to the synovial cavity and metalloproteinase release [92]. Moreover, the activation of CB2 receptors inhibits IL-1β-induced activation of extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinase in RA fibroblast [92].

The role of cannabinoid in neutrophils was also studied in ischemic models. Endocannabinoids act via the CB2 receptor in the modulation of the inflammatory response and myocardial remodeling after infarction. CB2 receptor plays an essential role in the formation of infarction border zone, collagen deposition, and organization of stable scar during remodeling. Duerr and coworkers [93] showed increased numbers of neutrophils in the heart ischemic area of CB2 receptor-deficient (Cnr2−/−) mice when compared with healthy mice. These results suggest that CB2 receptor modulates neutrophil migration to inflammatory infarction site [93]. In accordance, activation of the cannabinoid CB2 receptor by JWH-133 protects against atherosclerotic plaque formation and may also decrease neutrophil MMP-9 release, which reduces the vulnerability of ischemic stroke plaque in arteries. Together, the studies suggest that CB2 agonists represent a promising anti-atherosclerotic treatment [84].

Even though CB1 is the most prominent receptor in the CNS, CB2 modulates neuroinflammation. CB2 activation by JWH-133 reduced the number of neutrophils in the ischemic brain. Furthermore, CB2 activation in vitroinhibits adherence of neutrophils to brain endothelial cells. JWH-133 also interfered with the migration of neutrophils induced by the endogenous chemokine CXCL2 through activation of the MAP kinase p38. This effect on neutrophils is probably responsible for the neuroprotection mediated by JWH-133 [56].

3.3. Neutrophils, cannabinoid system, and infection

The relation between neutrophil and infection is well established [94]. On one hand, the exacerbation of neutrophil activation could lead to tissue damage. On the other hand, neutrophils control microorganism growth. In this context, it is essential to study the effect of cannabinoids on neutrophils during infections and evaluate if and how the cannabinoid system modulates neutrophil activity.

The interest in the relationship among cannabinoids and infections exists since the 1960s when studies regarding “hippie subculture” observed the increase of sexually transmitted infections by marijuana consumers [95]. By this time, the studies focused on consumer behavior and how it could increase susceptibility to infections but did not evaluate the effect of cannabinoids on host response to infections [96]. Nowadays, it is known that endocannabinoid system regulates and is regulated by host microbiota, a balance that protects the host from the infection-triggered inflammatory response [29]. However, the increase of studies showing the immunoregulatory role of the endocannabinoid system raises questions about if cannabinoids could modulate microbial viability and/or neutrophil response during infections.

Studies concerning the modulation of neutrophil activity by cannabinoids during infections are mostly addressed to experimental bacterial infection as sepsis model. Neutrophil activity during experimental sepsis is well characterized in studies in vivo(to review [97, 98, 99]). By using LPS sepsis model, Smith and coworkers showed that treatment with cannabinoid receptor agonists reduced the migration of neutrophils in the peritoneal cavity by inhibiting neutrophil chemoattractant production [59]. The authors conclude that CB2 was responsible for impairing neutrophil migration. In accordance, studies performed in CB2-deficient mice submitted to sepsis induced by cecal ligation and puncture showed increased production of neutrophil chemotactic chemokines and increased numbers of neutrophil in the bone marrow and lung tissue. Interestingly, despite the increase in neutrophil numbers, neutrophils from CB2-deficient mice were not able to activate the MAPK pathway neither control bacterial load [57, 100]. Furthermore, in mycobacteria model of infection, it was observed that CB2 agonism impairs neutrophil adhesion to endothelial cells probably by inhibiting actin polymerization [83].

There are few and controverting data concerning CB1 effects on neutrophils during infection. Leite-Avalca and coworkers showed that CB1 antagonist given to mice submitted to CLP increased the survival rate but not change neutrophil accumulation in the peritoneal cavity [101]. Nevertheless, Kianian and coworkers showed that antagonism of CB1 reduced the adhesion of leukocytes to intestinal submucosal venules [102]. It is noteworthy that in the sepsis model, the activation of CB1 increases the systemic arterial pressure and the flow and decreases the arterial oxygenation; however, it decreases the inflammatory cytokine production [103, 104]. In such a way, an indirect effect of CB1 on leukocyte behavior during sepsis cannot be ruled out.

The results regarding the immunomodulatory effects of cannabinoids in infection are in accordance with the host-directed therapy approach that aims to activate protective responses against microbes in addition to antimicrobial therapy [105]. However, it should be mentioned that antibiotics perturb gut microflora, which could result in the endocannabinoid system unbalance and, thus, in neuropsychiatric disorders [29]. Indeed, further studies are necessary to propose to activate the endocannabinoid system, especially the CB2 pathway, during infections.

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4. Conclusion

An increasing amount of data concerning the immunoregulatory role of cannabinoids, especially the CB2 agonists, has been raising the interest in developing new therapeutic strategies for inflammatory diseases. It is already known that the mechanism of action of well-established anti-inflammatory drugs, like paracetamol, depends on the activation of the endocannabinoid system [29]. However, despite all studies showing that cannabinoids can modulate neutrophil biology, there is a long way to go to achieve cannabinoid-based drugs to treat neutrophil-dependent diseases such as arthritis and infection-induced acute lung injury.

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Acknowledgments

The authors express their gratitude to Luana Barbosa Correa at the Laboratory of Applied Pharmacology (Farmanguinhos, FIOCRUZ) for her support in drawing Figure 2. This work was supported by grants from the Brazilian Council for Scientific and Technological Development (CNPq), Carlos Chagas Filho, Rio de Janeiro State Research Supporting Foundation (FAPERJ), and Oswaldo Cruz Foundation (FIOCRUZ).

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Conflict of interest

The authors declare no conflicts of interest.

References

  1. 1. Soehnlein O, Steffens S, Hidalgo A, Weber C. Neutrophils as protagonists and targets in chronic inflammation. Nature Reviews. Immunology. 2017;17(4):248-261
  2. 2. Salzet M, Breton C, Bisogno T, Di Marzo V. Comparative biology of the endocannabinoid system possible role in the immune response. European Journal of Biochemistry. 2000;267(16):4917-4927
  3. 3. Berdyshev EV. Cannabinoid receptors and the regulation of immune response. Chemistry and Physics of Lipids. 2000;108(1-2):169-190
  4. 4. Pertwee RG. Pharmacological actions of cannabinoids. Handbook of Experimental Pharmacology. 2005;168:1-51
  5. 5. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacological Reviews. 2002;54(2):161-202
  6. 6. Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Medical Journal. 2013;4(4):e0022
  7. 7. Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in cancer: Current status and future implications. Oncotarget. 2014;5(15):5852-5872
  8. 8. Rossi S, Bernardi G, Centonze D. The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis. Experimental Neurology. 2010;224(1):92-102
  9. 9. Immenschuh S. Endocannabinoid signalling as an anti-inflammatory therapeutic target in atherosclerosis: Does it work? Cardiovascular Research. 2009;84:341-342
  10. 10. Fukuda S, Kohsaka H, Takayasu A, Yokoyama W, Miyabe C, Miyabe Y, et al. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskeletal Disorders. 2014;15:275
  11. 11. Lehmann C, Kianian M, Zhou J, Kuster I, Kuschnereit R, Whynot S, et al. Cannabinoid receptor 2 activation reduces intestinal leukocyte recruitment and systemic inflammatory mediator release in acute experimental sepsis. Critical Care. 2012;16(2):R47
  12. 12. Schwartz RH, Beveridge RA. Marijuana as an antiemetic drug: How useful is it today? Opinions from clinical oncologists. Journal of Addictive Diseases. 1994;13(1):53-65
  13. 13. Mimura T, Oka S, Koshimoto H, Ueda Y, Watanabe Y, Sugiura T. Involvement of the endogenous cannabinoid 2 ligand 2-arachidonyl glycerol in allergic inflammation. International Archives of Allergy and Immunology. 2012;159(2):149-156
  14. 14. Lambert DM, Fowler CJ. The endocannabinoid system: Drug targets, lead compounds, and potential therapeutic applications. Journal of Medicinal Chemistry. 2005;48(16):5059-5087
  15. 15. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946-1949
  16. 16. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology. 1995;50(1):83-90
  17. 17. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochemical and Biophysical Research Communications. 1995;215(1):89-97
  18. 18. Bisogno T, Ligresti A, Di Marzo V. The endocannabinoid signalling system: Biochemical aspects. Pharmacology, Biochemistry, and Behavior. 2005;81(2):224-238
  19. 19. Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cellular and Molecular Life Sciences. 2016;73(23):4449-4470
  20. 20. Di Iorio G, Lupi M, Sarchione F, Matarazzo I, Santacroce R, Petruccelli F, et al. The endocannabinoid system: A putative role in neurodegenerative diseases. International Journal of High Risk Behaviors and Addiction. 2013;2(3):100-106
  21. 21. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends in Pharmacological Sciences. 2009;30(10):515-527
  22. 22. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol, and delta9-tetrahydrocannabivarin. British Journal of Pharmacology. 2008;153(2):199-215
  23. 23. Veiga Junior VF, Rosas EC, Carvalho MV, Henriques MG, Pinto AC. Chemical composition and anti-inflammatory activity of copaiba oils from Copaifera cearensis Huber ex Ducke, Copaifera reticulata Ducke and Copaifera multijuga Hayne—A comparative study. Journal of Ethnopharmacology. 2007;112(2):248-254
  24. 24. Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the cannabis plant—Do they exist? British Journal of Pharmacology. 2010;160(3):523-529
  25. 25. Sharma C, Sadek B, Goyal SN, Sinha S, Kamal MA, Ojha S. Small molecules from nature targeting G-protein coupled cannabinoid receptors: Potential leads for drug discovery and development. Evidence-based Complementary and Alternative Medicine. 2015;2015:238482
  26. 26. Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, et al. Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9099-9104
  27. 27. Gertsch J. Immunomodulatory lipids in plants: Plant fatty acid amides and the human endocannabinoid system. Planta Medica. 2008;74(6):638-650
  28. 28. Han S, Thatte J, Buzard DJ, Jones RM. Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. Journal of Medicinal Chemistry. 2013;56(21):8224-8256
  29. 29. Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nature Reviews. Drug Discovery. 2018;17(9):623-639
  30. 30. Howlett AC. Cannabinoid receptor signaling. Handbook of Experimental Pharmacology. 2005;168:53-79
  31. 31. Bosier B, Muccioli GG, Hermans E, Lambert DM. Functionally selective cannabinoid receptor signalling: Therapeutic implications and opportunities. Biochemical Pharmacology. 2010;80(1):1-12
  32. 32. Dhopeshwarkar A, Mackie K. CB2 cannabinoid receptors as a therapeutic target—What does the future hold? Molecular Pharmacology. 2014;86(4):430-437
  33. 33. Correa F, Docagne F, Mestre L, Clemente D, Hernangomez M, Loria F, et al. A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. Biochemical Pharmacology. 2009;77(1):86-100
  34. 34. Correa F, Mestre L, Docagne F, Guaza C. Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: Role of IL-10 and ERK1/2 kinase signaling. British Journal of Pharmacology. 2005;145(4):441-448
  35. 35. Correa F, Hernangomez M, Mestre L, Loria F, Spagnolo A, Docagne F, et al. Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: Roles of ERK1/2, JNK, and NF-kappaB. Glia. 2010;58(2):135-147
  36. 36. Rajesh M, Mukhopadhyay P, Hasko G, Huffman JW, Mackie K, Pacher P. CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. British Journal of Pharmacology. 2008;153(2):347-357
  37. 37. Borner C, Smida M, Hollt V, Schraven B, Kraus J. Cannabinoid receptor type 1- and 2-mediated increase in cyclic AMP inhibits T cell receptor-triggered signaling. The Journal of Biological Chemistry. 2009;284(51):35450-35460
  38. 38. Howlett AC, Shim JY. Cannabinoid Receptors and Signal Transduction. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from:https://www.ncbi.nlm.nih.gov/books/NBK6154/
  39. 39. Fride E, Foox A, Rosenberg E, Faigenboim M, Cohen V, Barda L, et al. Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: Evidence for a “CB3” receptor. European Journal of Pharmacology. 2003;461(1):27-34
  40. 40. Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH. Cannabinoid receptor-related orphan G protein-coupled receptors. Advances in Pharmacology. 2017;80:223-247
  41. 41. Liu J, Li H, Burstein SH, Zurier RB, Chen JD. Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Molecular Pharmacology. 2003;63(5):983-992
  42. 42. Ambrosio AL, Dias SM, Polikarpov I, Zurier RB, Burstein SH, Garratt RC. Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma. The Journal of Biological Chemistry. 2007;282(25):18625-18633
  43. 43. O’Sullivan SE. Cannabinoids go nuclear: Evidence for activation of peroxisome proliferator-activated receptors. British Journal of Pharmacology. 2007;152(5):576-582
  44. 44. Abood ME, Martin BR. Neurobiology of marijuana abuse. Trends in Pharmacological Sciences. 1992;13(5):201-206
  45. 45. Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. The European Journal of Neuroscience. 1999;11(12):4213-4225
  46. 46. Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology. 1988;34(5):605-613
  47. 47. Hernandez-Cervantes R, Mendez-Diaz M, Prospero-Garcia O, Morales-Montor J. Immunoregulatory role of cannabinoids during infectious disease. Neuroimmunomodulation. 2017;24(4-5):183-199
  48. 48. Deng L, Guindon J, Cornett BL, Makriyannis A, Mackie K, Hohmann AG. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biological Psychiatry. 2015;77(5):475-487
  49. 49. Navarro G, Morales P, Rodriguez-Cueto C, Fernandez-Ruiz J, Jagerovic N, Franco R. Targeting cannabinoid CB2 receptors in the central nervous system. Medicinal chemistry approaches with focus on neurodegenerative disorders. Frontiers in Neuroscience. 2016;10:406
  50. 50. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, et al. Cannabinoid-receptor expression in human leukocytes. European Journal of Biochemistry. 1993;214(1):173-180
  51. 51. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. European Journal of Biochemistry. 1995;232(1):54-61
  52. 52. Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA. Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. International Immunopharmacology. 2002;2(1):69-82
  53. 53. Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nature Reviews. Immunology. 2005;5(5):400-411
  54. 54. Bento AF, Marcon R, Dutra RC, Claudino RF, Cola M, Leite DF, et al. Beta-caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARgamma pathway. The American Journal of Pathology. 2011;178(3):1153-1166
  55. 55. Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(−/−) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicology and Applied Pharmacology. 2012;258(2):256-267
  56. 56. Murikinati S, Juttler E, Keinert T, Ridder DA, Muhammad S, Waibler Z, et al. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. The FASEB Journal. 2010;24(3):788-798
  57. 57. Tschop J, Kasten KR, Nogueiras R, Goetzman HS, Cave CM, England LG, et al. The cannabinoid receptor 2 is critical for the host response to sepsis. Journal of Immunology. 2009;183(1):499-505
  58. 58. Toguri JT, Lehmann C, Laprairie RB, Szczesniak AM, Zhou J, Denovan-Wright EM, et al. Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis. British Journal of Pharmacology. 2014;171(6):1448-1461
  59. 59. Smith SR, Denhardt G, Terminelli C. The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models. European Journal of Pharmacology. 2001;432(1):107-119
  60. 60. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity. 2002;17(4):413-423
  61. 61. Sadik CD, Kim ND, Luster AD. Neutrophils cascading their way to inflammation. Trends in Immunology. 2011;32(10):452-460
  62. 62. Balenga NA, Aflaki E, Kargl J, Platzer W, Schroder R, Blattermann S, et al. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Research. 2011;21(10):1452-1469
  63. 63. Pillinger MH, Abramson SB. The neutrophil in rheumatoid arthritis. Rheumatic Diseases Clinics of North America. 1995;21(3):691-714
  64. 64. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell. 1994;76(2):301-314
  65. 65. Bokoch GM. Regulation of innate immunity by rho GTPases. Trends in Cell Biology. 2005;15(3):163-171
  66. 66. Graham ES, Angel CE, Schwarcz LE, Dunbar PR, Glass M. Detailed characterisation of CB2 receptor protein expression in peripheral blood immune cells from healthy human volunteers using flow cytometry. International Journal of Immunopathology and Pharmacology. 2010;23(1):25-34
  67. 67. Derocq JM, Jbilo O, Bouaboula M, Segui M, Clere C, Casellas P. Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible involvement of the CB2 receptor in cell differentiation. The Journal of Biological Chemistry. 2000;275(21):15621-15628
  68. 68. Alberich Jorda M, Rayman N, Tas M, Verbakel SE, Battista N, van Lom K, et al. The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. Blood. 2004;104(2):526-534
  69. 69. Kurihara R, Tohyama Y, Matsusaka S, Naruse H, Kinoshita E, Tsujioka T, et al. Effects of peripheral cannabinoid receptor ligands on motility and polarization in neutrophil-like HL60 cells and human neutrophils. The Journal of Biological Chemistry. 2006;281(18):12908-12918
  70. 70. McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: Evidence for a site distinct from CB1 and CB2. Molecular Pharmacology. 2008;73(2):441-450
  71. 71. Berdyshev E, Boichot E, Corbel M, Germain N, Lagente V. Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice. Life Sciences. 1998;63(8):Pl125-Pl129
  72. 72. Jorda MA, Rayman N, Valk P, De Wee E, Delwel R. Identification, characterization, and function of a novel oncogene: The peripheral cannabinoid receptor Cb2. Annals of the New York Academy of Sciences. 2003;996:10-16
  73. 73. Mukhopadhyay P, Rajesh M, Horvath B, Batkai S, Park O, Tanchian G, et al. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radical Biology & Medicine. 2011;50(10):1368-1381
  74. 74. Wang Y, Mukhopadhyay P, Cao Z, Wang H, Feng D, Hasko G, et al. Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury. Scientific Reports. 2017;7(1):12064
  75. 75. Ribeiro A, Ferraz-de-Paula V, Pinheiro ML, Vitoretti LB, Mariano-Souza DP, Quinteiro-Filho WM, et al. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: Role for the adenosine A(2A) receptor. European Journal of Pharmacology. 2012;678(1-3):78-85
  76. 76. Napimoga MH, Benatti BB, Lima FO, Alves PM, Campos AC, Pena-Dos-Santos DR, et al. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. International Immunopharmacology. 2009;9(2):216-222
  77. 77. Thapa D, Cairns EA, Szczesniak AM, Toguri JT, Caldwell MD, Kelly MEM. The cannabinoids Delta(8)THC, CBD, and HU-308 act via distinct receptors to reduce corneal pain and inflammation. Cannabis and Cannabinoid Research. 2018;3(1):11-20
  78. 78. Makwana R, Venkatasamy R, Spina D, Page C. The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough. The Journal of Pharmacology and Experimental Therapeutics. 2015;353(1):169-180
  79. 79. Li W, Huang H, Niu X, Fan T, Mu Q, Li H. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice. Toxicology and Applied Pharmacology. 2013;272(1):21-29
  80. 80. Horvath B, Mukhopadhyay P, Kechrid M, Patel V, Tanchian G, Wink DA, et al. Beta-caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radical Biology & Medicine. 2012;52(8):1325-1333
  81. 81. Medeiros R, Passos GF, Vitor CE, Koepp J, Mazzuco TL, Pianowski LF, et al. Effect of two active compounds obtained from the essential oil of Cordia verbenacea on the acute inflammatory responses elicited by LPS in the rat paw. British Journal of Pharmacology. 2007;151(5):618-627
  82. 82. Varga ZV, Matyas C, Erdelyi K, Cinar R, Nieri D, Chicca A, et al. Beta-caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. British Journal of Pharmacology. 2018;175(2):320-334
  83. 83. Andrade-Silva M, Correa LB, Candea AL, Cavalher-Machado SC, Barbosa HS, Rosas EC, et al. The cannabinoid 2 receptor agonist beta-caryophyllene modulates the inflammatory reaction induced byMycobacterium bovisBCG by inhibiting neutrophil migration. Inflammation Research. 2016;65(11):869-879
  84. 84. Montecucco F, Di Marzo V, da Silva RF, Vuilleumier N, Capettini L, Lenglet S, et al. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. European Heart Journal. 2012;33(7):846-856
  85. 85. Nilsson O, Fowler CJ, Jacobsson SO. The cannabinoid agonist WIN 55,212-2 inhibits TNF-alpha-induced neutrophil transmigration across ECV304 cells. European Journal of Pharmacology. 2006;547(1-3):165-173
  86. 86. Hasenoehrl C, Storr M, Schicho R. Cannabinoids for treating inflammatory bowel diseases: Where are we and where do we go? Expert Review of Gastroenterology & Hepatology. 2017;11(4):329-337
  87. 87. Borrelli F, Fasolino I, Romano B, Capasso R, Maiello F, Coppola D, et al. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochemical Pharmacology. 2013;85(9):1306-1316
  88. 88. Schicho R, Bashashati M, Bawa M, McHugh D, Saur D, Hu HM, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflammatory Bowel Diseases. 2011;17(8):1651-1664
  89. 89. Uranga JA, Vera G, Abalo R. Cannabinoid pharmacology and therapy in gut disorders. Biochemical Pharmacology. 2018;157:134-147
  90. 90. Rosas E, Correa L, MdG H. In: Khajah MA, editor. Neutrophils in Rheumatoid Arthritis: A Target for Discovering New Therapies Based on Natural Products. 1st ed. Rijeka, Croatia: IntechOpen; 2017. pp. 89-118
  91. 91. Richardson D, Pearson RG, Kurian N, Latif ML, Garle MJ, Barrett DA, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Research & Therapy. 2008;10(2):R43
  92. 92. Gui H, Liu X, Wang ZW, He DY, Su DF, Dai SM. Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford, England). 2014;53(5):802-809
  93. 93. Duerr GD, Heinemann JC, Gestrich C, Heuft T, Klaas T, Keppel K, et al. Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice. Life Sciences. 2015;138:8-17
  94. 94. Kobayashi SD, Voyich JM, DeLeo FR. Regulation of the neutrophil-mediated inflammatory response to infection. Microbes and Infection. 2003;5(14):1337-1344
  95. 95. Linken A. A study of drug-taking among young patients attending a clinic for venereal diseases. The British Journal of Venereal Diseases. 1968;44(4):337-341
  96. 96. Smith D, Rose AJ. Observations in the Haight-Ashbury Medical Clinic of San Francisco. Health problems in a “hippie” subculture. Clinical Pediatrics (Phila). 1968;7(6):313-316
  97. 97. Sonego F, Castanheira FV, Ferreira RG, Kanashiro A, Leite CA, Nascimento DC, et al. Paradoxical roles of the neutrophil in sepsis: Protective and deleterious. Frontiers in Immunology. 2016;7:155
  98. 98. Zhang H, Sun B. Pleiotropic regulations of neutrophil receptors response to sepsis. Inflammation Research. 2017;66(3):197-207
  99. 99. Shen XF, Cao K, Jiang JP, Guan WX, Du JF. Neutrophil dysregulation during sepsis: An overview and update. Journal of Cellular and Molecular Medicine. 2017;21(9):1687-1697
  100. 100. Kapellos TS, Recio C, Greaves DR, Iqbal AJ. Cannabinoid receptor 2 modulates neutrophil recruitment in a murine model of endotoxemia. Mediators of Inflammation. 2017;2017:4315412
  101. 101. Leite-Avalca MC, Lomba LA, Bastos-Pereira AL, Brito HO, Fraga D, Zampronio AR. Involvement of central endothelin ETA and cannabinoid CB1 receptors and arginine vasopressin release in sepsis induced by cecal ligation and puncture in rats. Shock. 2016;46(3):290-296
  102. 102. Kianian M, Kelly ME, Zhou J, Hung O, Cerny V, Rowden G, et al. Cannabinoid receptor 1 inhibition improves the intestinal microcirculation in experimental endotoxemia. Clinical Hemorheology and Microcirculation. 2014;58(2):333-342
  103. 103. Kadoi Y, Hinohara H, Kunimoto F, Kuwano H, Saito S, Goto F. Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats. British Journal of Anaesthesia. 2005;94(5):563-568
  104. 104. Kadoi Y, Goto F. Effects of AM281, a cannabinoid antagonist, on circulatory deterioration and cytokine production in an endotoxin shock model: Comparison with norepinephrine. Journal of Anesthesia. 2006;20(4):284-289
  105. 105. Kaufmann SHE, Dorhoi A, Hotchkiss RS, Bartenschlager R. Host-directed therapies for bacterial and viral infections. Nature Reviews. Drug Discovery. 2018;17(1):35-56

Written By

Mariana Conceição Souza and Elaine Cruz Rosas

Submitted: May 16th, 2018 Reviewed: October 12th, 2018 Published: November 27th, 2018