Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway

• Published in: Redox biology 2018-04, Vol.14, p.600-608
• Main Authors: Hou, Liyan, Bao, Xiuqi, Zang, Caixia, Yang, Hanyu, Sun, Fuqiang, Che, Yuning, Wu, Xuefei, Li, Shao, Zhang, Dan, Wang, Qingshan
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - immunology; Animals; CD11b; CD11b Antigen - immunology; Cells, Cultured; Humans; Inflammation - immunology; Integrin αMβ2; Male; Mice; Mice, Inbred C57BL; Microglia - immunology; NADPH oxidase; NADPH Oxidase 2 - immunology; Research Paper; rho GTP-Binding Proteins - immunology; rhoA GTP-Binding Protein; Signal Transduction; Synucleinopathy; α-Synuclein
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2017.11.010

The activation of microglial NADPH oxidase (NOX2) induced by α-synuclein has been implicated in Parkinson's disease (PD) and other synucleinopathies. However, how α-synuclein activates NOX2 remains unclear. Previous study revealed that both toll-like receptor 2 (TLR2) and integrin play important roles in α-synuclein-induced microglial activation. In this study, we found that blocking CD11b, the α chain of integrin αMβ2, but not TLR2 attenuated α-synuclein-induced NOX2 activation in microglia. The involvement of CD11b in α-synuclein-induced activation of NOX2 was further confirmed in CD11b-/- microglia by showing reduced membrane translocation of NOX2 cytosolic subunit p47phox and superoxide production. Mechanistically, α-synuclein bound to CD11b and subsequently activated Rho signaling pathway. α-Synuclein induced activation of RhoA and downstream ROCK but not Rac1 in a CD11b-dependent manner. Moreover, siRNA-mediated knockdown of RhoA impeded NOX2 activation in response to α-synuclein. Furthermore, we found that inhibition of NOX2 failed to interfere with the activation of RhoA signaling and interactions between α-synuclein and CD11b, further confirming that NOX2 was the downstream target of CD11b. Finally, we found that genetic deletion of CD11b abrogated α-synuclein-induced NOX2 activatoin in vivo. Taken together, our results indicated that integrin CD11b mediates α-synuclein-induced NOX2 activation through a RhoA-dependent pathway, providing not only a novel mechanistic insight but also a new potential therapeutic target for synucleinopathies. [Display omitted] •Blocking CD11b, the α chain of integrin αMβ2, but not TLR2 attenuates α-synuclein-induced NOX2 activation.•α-Synuclein binds to CD11b.•CD11b regulates NOX2 activation induced by α-synuclein through a RhoA-dependent pathway.