Original Article

Age-related differences in interferon regulatory factor-4 and -5 signaling in ischemic brains of mice

Authors: ZHAO Shou-cai, WANG Chun, XU Heng, WU Wen-qian, CHU Zhao-hu, MA Ling-song, ZHANG Ying-dong, LIU Fudong
Corresponding to: ZHAO Shou-cai
DOI: 10.1038/aps.2017.122

Abstract

Stroke is a disease that mainly affects the elderly and modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure where microglial activation plays an important role. Interferon regulatory factor-5 (IRF5) and IRF4 regulate M1 and M2 activation of macrophages, respectively, in peripheral inflammation; but it is unknown whether IRF5/IRF4 are also involved in cerebral inflammatory responses to stroke and whether age-related differences of the IRF5/IRF4 signaling exist in the ischemic brain. Here, we investigated the impacts of aging on IRF5/IRF4 signaling and poststroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subject to middle cerebral artery occlusion (MCAO). Morphological and biochemical changes in the ischemic brains and behavior deficits were assessed on 1, 3, and 7 d post-stroke. After MCAO, the aged mice showed smaller infarct sizes but worse behavior deficits than young mice. Young mice had significantly more IRF4/CD206 double positive microglia in the ischemic brains, whereas the aged mice had more IRF5+ and MHCII+ microglia after stroke than their counterparts. In addition, serum pro-inflammatory cytokines (TNF-α, iNOS, IL-6) were more robustly up-regulated in aged mice, whereas serum anti-inflammatory cytokine (TGF-β, IL-4, IL-10) levels were higher in young mice compared to their counterparts after MCAO. Our results demonstrate that aging has a significant effect on stroke outcomes in mice, which is most likely mediated by age-specific inflammatory responses.
Keywords: stroke; MCAO; aging; microglia; IRF4; IRF5; cytokines; neuroinflammation