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

Abstract

Stroke is a disease that mainly affects the elderly. Since the age-related differences in stroke have not been well studied, modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure, in which 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 ischemic brain. Here, we investigated the influences of aging on IRF5/IRF4 signaling and post-stroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subjected 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 higher neurological deficits and corner test scores than young mice. Young mice had higher levels of IRF4 and CD206 microglia in the ischemic brains, whereas the aged mice expressed more IRF5 and MHCII microglia. After MCAO, serum pro-inflammatory cytokines (TNF-α, iNOS, IL-6) were more prominently up-regulated in aged mice, whereas serum anti-inflammatory cytokines (TGF-β, IL-4, IL-10) were more prominently up-regulated in young mice. Our results demonstrate that aging has a significant influence on stroke outcomes in mice, which is probably mediated by age-specific inflammatory responses.

A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes

“…IRF5 induces the expression of pro-inflammatory factors and promotes the M1 polarization of macrophages [ 46 , 47 ]. More recently, it has been proposed that the balance between IRF5 and IRF4 influences microglial activity and corresponds to infarct size and neurological deficits [ 48 , 49 ]. In our model system, IRF5/IRF4 ratios were significantly higher in endothelial-activated microglia compared to astrocyte-activated microglia, consistent with potentially deleterious properties of the former versus the latter.…”

Potential microglia‐based interventions for stroke

“…In mice, aging has been proven to have a significant influence on stroke outcomes, which is likely associated with age‐specific inflammatory responses . Studies have demonstrated that aging is an important determinant of stroke outcomes and is positively correlated with worsened functional recovery after stroke . Different cellular and molecular responses to stroke in aged microglia versus young microglia have been reported.…”

“…For instance, there are higher numbers of interferon regulatory factor 4 (IRF4)‐ and CD206‐positive microglia in the ischemic brains of young mice, whereas aged mice express more IRF5 and major histocompatibility complex class II (MHCII) on microglia. In addition, serum anti‐inflammatory cytokines, including transforming growth factor beta (TGF‐β), interleukin (IL)‐4, and IL‐10, are more prominently upregulated in young mice after middle cerebral artery occlusion (MCAO), whereas proinflammatory cytokines (TNF‐α, iNOS, and IL‐6) are more prominently upregulated in aged mice . Therefore, targeting aging microglia or rejuvenating them in stroke patients may represent a promising therapeutic strategy.…”

“…18 Studies have demonstrated that aging is an important determinant of stroke outcomes and is positively correlated with worsened functional recovery after stroke. 19 Different cellular and molecular responses to stroke in aged microglia versus young microglia have been reported. For instance, there are higher numbers of interferon regulatory factor 4 (IRF4)-and CD206-positive microglia in the ischemic brains of young mice, whereas aged mice express more IRF5 and major histocompatibility complex class II (MHCII) on microglia.…”

“…In addition, serum anti-inflammatory cytokines, including transforming growth factor beta (TGFβ), interleukin (IL)-4, and IL-10, are more prominently upregulated in young mice after middle cerebral artery occlusion (MCAO), whereas proinflammatory cytokines (TNF-α, iNOS, and IL-6) are more prominently upregulated in aged mice. 19 Therefore, targeting aging microglia or rejuvenating them in stroke patients may represent a promising therapeutic strategy. Physical exercise after stroke was found to be a therapeutic approach targeting microglia in aged MCAO mice.…”