Role Of Myeloid Lineage Cell Autophagy In Ischemic Brain Injury
Background and Purpose-Inflammatory cells play a significant role in secondary injury after ischemic stroke. Recent studies have suggested that a lack of autophagy in myeloid cells causes augmented proinflammatory cytokine release and prolonged inflammation after tissue injury. In this study, we investigated the roles of myeloid cell autophagy in ischemic brain injury. Methods-Focal cerebral ischemia was induced via transient middle cerebral artery occlusion in mice with autophagydeficient myeloid lineage cells (Atg5flox/flox LysMCre+) and in their littermate controls (Atg5flox/flox). Infarct volume, neurological function, inflammatory cell infiltration, and proinflammatory cytokine expression levels were evaluated. Results-Mice lacking autophagy in myeloid lineage cells had a lower survival rate for 14 days than control mice (20% versus 70%; P<0.05). Although there was no difference in infarct volume at 12 hours between the 2 groups, mice lacking autophagy in myeloid lineage cells had larger infarct volumes at later time points (3 and 7 days after reperfusion) with worse neurological deficit scores and lower grip test scores. There were a higher number of ionized calcium binding adaptor molecule 1-positive cells and cells expressing M1 marker CD16/32 in mice lacking autophagy in myeloid cells at the later time points. Moreover, these mice had higher expression levels of proinflammatory cytokines at later time points; however, there was no difference in ionized calcium binding adaptor molecule 1-positive cells or mRNA levels of proinflammatory cytokines at the earlier time point (12 hours after reperfusion). Conclusions-These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.
Digital Object Identifier (DOI)
Kotoda, Masakazu; Furukawa, Hajime; Miyamoto, Takeshi; Korai, Masaaki; Shikata, Fumiaki; Kuwabara, Atsushi; Xiong, Xiaoxing; Rutledge, Caleb; Giffard, Rona G.; and Hashimoto, Tomoki, "Role Of Myeloid Lineage Cell Autophagy In Ischemic Brain Injury" (2018). Translational Neuroscience. 102.