Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model.
Excessive inflammatory responses are involved in secondary brain injury during germinal matrix hemorrhage (GMH). The process of microglial polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes is considered to occur in a major immunomodulatory manner during brain inflammation. We previously found that cannabinoid receptor-2 (CB2R) stimulation attenuated microglial accumulation and brain injury following experimental GMH. However, whether CB2R has effects on microglial polarization after GMH remains unclear. Herein, we investigated the effects of CB2R stimulation on neuroinflammation after experimental GMH and the potential mechanisms that mediate M1/M2 microglial phenotype regulation. The results indicated that during the GMH acute phase, microglia primarily polarized to the M1 phenotype and induced an overwhelming release of pro-inflammatory cytokines. However, JWH133, a selective CB2R agonist, significantly prevented the pro-inflammatory cytokine release while promoting an M1 to M2 phenotype transformation in microglia, resulting in an increased anti-inflammatory cytokine release. Moreover, in thrombin-induced rat primary microglial cells, JWH133 reduced the pro-inflammatory cytokine levels and M1 phenotype by enhancing the acquisition of the M2 phenotype. Additionally, JWH133 facilitated synthesis of cyclic AMP (cAMP) and its downstream effectors, phosphorylated cAMP-dependent protein kinase (p-PKA) and exchange protein activated by cyclic-AMP 1 (Epac1). The promoting effects of JWH133 on M2 polarization were attenuated with a specific PKA inhibitor but not with an Epac inhibitor, indicating that the cAMP/PKA signaling pathway was involved in the JWH133 effects. This is the first study to propose that promotion of microglial M2 polarization through the cAMP/PKA pathway participates in the CB2R-mediated anti-inflammatory effects after GMH induction. The results will help to further understand the mechanisms that underlie neuroprotection by CB2R in GMH and promote clinical translational research for CB2R agonists.
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Yihao
Y
Tao
Department of Neurosurgery, Nanchong Central Hospital, Nanchong 637000, China.
Lin
L
Li
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Bing
B
Jiang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Zhou
Z
Feng
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Liming
L
Yang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Jun
J
Tang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Qianwei
Q
Chen
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Jianbo
J
Zhang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Qiang
Q
Tan
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Hua
H
Feng
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: zhichen@tmmu.edu.cn.
Zhi
Z
Chen
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: gangzhu6666@sina.com.
Gang
G
Zhu
D000818:Animals; D016764:Cell Polarity; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology* / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
Anti-inflammation; Cannabinoid receptor-2; Microglial polarization; PKA