Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

Alferink, Judith; Specht, Sabine; Arends, Hannah; Schumak, Beatrix; Schmidt, Kim E.; Ruland, Christina; Lundt, Ramona; Kemter, Andrea M.; Dlugos, Andrea; Kuepper, Janina M.; Poppensieker, Karola; Findeiss, Matthias; Albayram, Önder; Otte, David-M.; Marazzi, Janine; Gertsch, Jürg; Förster, Irmgard; Maier, Wolfgang; Scheu, Stefanie; Hoerauf, Achim; Zimmer, Andreas

doi:10.1074/jbc.m116.746594

Cited by 23 publications

(21 citation statements)

References 69 publications

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“…In vitro, microglial expression of CB 2 receptors is the subject of pathogen-or cytokine-specific regulation [87][88][89]. In a mouse model of cerebral malaria, the CB 2 knockout was also associated with a reduced inflammatory status, highlighting the model-dependent role of CB 2 function [90]. A possible explanation for the discrepancies might be compensatory amplified signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures

2020

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Abnormal cannabidiol (abn-CBD) exerts neuroprotective effects in vivo and in vitro. In the present study, we investigated the impact of abn-CBD on the glial production of proinflammatory mediators and scar formation within in vitro models. Primary astrocytic-microglial cocultures and astrocytic cultures from neonatal C57BL/6 mice and CB2 receptor knockout mice were stimulated with lipopolysaccharide (LPS), and the concentrations of tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and nitrite were determined. Furthermore, we performed a live cell microscopy-based scratch-wound assay. After LPS stimulation, TNFα, IL-6 and nitrite production was more strongly increased in cocultures than in isolated astrocytes. Abn-CBD treatment attenuated the LPS-induced production of TNFα and nitrite in cocultures, while IL-6 production remained unaltered. In isolated astrocytes, only LPS-induced TNFα production was reduced by abn-CBD. Similar effects were observed after abn-CBD application in cocultures of CB2 knockout mice. Interestingly, LPS-induced TNFα and nitrite levels were far lower in CB2 knockout cultures compared to wildtypes, while IL-6 levels did not differ. In the scratch-wound assay, treatment with abn-CBD decelerated wound closure when microglial cells were present. Our data shows a differential role of abn-CBD for modulation of glial inflammation and astrocytic scar formation. These findings provide new explanations for mechanisms behind the neuroprotective potential of abn-CBD.

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Section: Discussionmentioning

confidence: 99%

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures

2020

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“…CBD, along with the antimalarial drug artesunate, is able to increase the survival rate of mice infected with Plasmodium berghei ANKA, and can prevent cognitive deficiency associated with the infection [100]. Interestingly, another study demonstrated that CB2 activation had no beneficial effect in an experimental murine model for cerebral malaria, as CB2 knockout mice presented with a higher survival rate due to a lower parasite load in the brain and lower expression of proinflammatory cytokines such as TNF-α and IFN-γ, in addition to lower hematoencephalic barrier disruption [101]. The mononuclear cell infiltrate was also lower, with fewer CD8+ lymphocytes, in contrast with CD11b+ cells which were found in a higher proportion.…”

Section: Plasmodium Bergheimentioning

confidence: 99%

Immunoregulatory Role of Cannabinoids during Infectious Disease

Hernández-Cervantes

Méndez-Dı́az²,

Prospéro-Garcı́a³

et al. 2017

Neuroimmunomodulation

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Although the endocannabinoid system (ECS) is involved in the regulation of several physiological processes, including sleep and the immune response, its role during infections has not been fully studied. It is well known that the use of this drug increases susceptibility to infections because of the impact on the modulation of the immune system. Concerning the medicinal or recreational use of marijuana, its influence on the course of an infection, whether this has been caused by bacteria, viruses, parasites, and to a lesser degree, fungi, has been reported. Furthermore, there is evidence suggesting the involvement of the ECS in the control and elimination of infectious agents such as bacteria, viruses, and some protozoa; in the case of fungi, few studies are available so far. The purpose of this review is to present the existing studies related to infections and the ECS, the microbicidal effects of compounds isolated from Cannabis sativa, and the association between marijuana use and the development of rare pathologies in specific diseases.

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“…CB2, which is derived from hematopoietic origin cells, mediates cannabinoid‐induced immune modulation . In addition, peripheral anti‐inflammatory effects of the endocannabinoid system are associated with signaling via CB2 . However, these two types of receptors are also important regulators for bone remodeling because they affect the proliferation, differentiation, and maturation of bone cells, such as osteoclasts, osteoblasts, and osteocytes .…”

Section: Introductionmentioning

confidence: 99%

“…(14) In addition, peripheral anti-inflammatory effects of the endocannabinoid system are associated with signaling via CB2. (15,16) However, these two types of receptors are also important regulators for bone remodeling because they affect the proliferation, differentiation, and maturation of bone cells, such as osteoclasts, osteoblasts, and osteocytes. (17)(18)(19)(20) Due to their unique combination of properties, cannabinoid receptors, especially CB2, have been widely studied for the treatment of inflammatory disorders and osteolytic bone damage.…”

Section: Introductionmentioning

confidence: 99%

“…(17)(18)(19)(20) Due to their unique combination of properties, cannabinoid receptors, especially CB2, have been widely studied for the treatment of inflammatory disorders and osteolytic bone damage. (15,20,21) Accumulating data indicate that the cannabinoid system is a crucial mediator in the pathogenesis of arthritis. Two of the best-known endocannabinoid ligands, anandamide and 2-arachidonylglycerol, have been detected in RA and osteoarthritis synovial tissue but not in healthy joints.…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Zhu

Bai

et al. 2018

Journal of Bone and Mineral Research

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Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen‐induced arthritis (CIA) mice synovium and bone tissues than in the noninflamed synovium and bone tissues. The CB2 selective agonist (JWH133) but not antagonist (SR144528) suppressed CIA in mice without toxic effects, as demonstrated by the decreased synovial hyperplasia, inflammatory responses, cartilage damage, and periarticular and systemic bone destruction. JWH133 treatment decreased the infiltration of pro‐inflammatory M1‐like macrophages and repolarized macrophages from the M1 to M2 phenotype. Similarly, activation of CB2 increased the expression of anti‐inflammatory cytokine interleukin (IL)‐10 and reduced the expression of pro‐inflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐1β, and IL‐6. In addition, JWH133 treatment attenuated osteoclast formation and osteoclastic bone resorption, and reduced the expression of receptor activators of the nuclear factor‐κB (NF‐κB) ligand (RANKL), matrix metallopeptidase‐9 (MMP‐9), tartrate‐resistant acid phosphatase (TRAP), cathepsin K (CTSK), and nuclear factor of activated T‐cells 1 (NFAT‐1) in CIA mice and osteoclast precursors, which were obviously blocked by pretreatment with SR144528. Mechanistically, JWH133 inhibited RANKL‐induced NF‐κB activation in the osteoclast precursors. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis. © 2018 American Society for Bone and Mineral Research.

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Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

Abstract: Cerebral malaria is a severe and often fatal complication of

Cited by 23 publications

References 69 publications

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures

Immunoregulatory Role of Cannabinoids during Infectious Disease

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

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