Central IRF4/5 Signaling Are Critical for Microglial Activation and Impact on Stroke Outcomes.
Central IRF4/5 Signaling Are Critical for Microglial Activation and Impact on Stroke Outcomes.
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DOI：
10.1007/s12975-023-01172-2
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发表时间：
2023-07
影响因子：
6.9
通讯作者：
Conelius Ngwa;Abdullah Al Mamun;Shaohua Qi;Romana Sharmeen;M. P. B. Conesa;B. Ganesh;B. Manwani;Fudong Liu
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作者：
Conelius Ngwa;Abdullah Al Mamun;Shaohua Qi;Romana Sharmeen;M. P. B. Conesa;B. Ganesh;B. Manwani;Fudong Liu
小胶质细胞和单核细胞在脑缺血的免疫反应中发挥关键作用。先前的研究已经证明干扰素调节因子4（IRF 4）和IRF 5指导中风后的小胶质细胞极化并影响结果。然而，IRF 4/5由小胶质细胞和单核细胞表达，并且不清楚在中风中起作用的是小胶质细胞（中央）还是单核细胞（外周）IRF 4-IRF 5调节轴。在这项工作中，使用年轻（8-12周）雄性pep boy（PB）、IRF 4或IRF 5 flox和IRF 4或IRF 5条件性敲除（CKO）小鼠产生8种类型的骨髓嵌合体，以区分中枢（PB-至-IRF CKO）与外周（IRF CKO-至-PB）吞噬细胞IRF 4-IRF 5轴在卒中中的作用。从PB和flox小鼠产生的嵌合体用作对照。所有嵌合体均进行60分钟大脑中动脉闭塞（MCAO）模型。中风后三天，分析结果和炎症反应。我们发现，PB至IRF 4 CKO嵌合体比IRF 4 CKO至PB嵌合体具有更强的小胶质细胞促炎反应，而在PB至IRF 5 CKO与IRF 5 CKO至PB嵌合体中观察到改善的小胶质细胞反应。IRF 4或IRF 5 CKO嵌合体的卒中结局分别比对照组更差或更好，而IRF 4或5 CKO至PB嵌合体的结局与对照组相似。我们的结论是，中央IRF 4/5信号是负责小胶质细胞激活和介导中风的结果。
Microglia and monocytes play a critical role in immune responses to cerebral ischemia. Previous studies have demonstrated that interferon regulatory factor 4 (IRF4) and IRF5 direct microglial polarization after stroke and impact outcomes. However, IRF4/5 are expressed by both microglia and monocytes, and it is not clear if it is the microglial (central) or monocytic (peripheral) IRF4-IRF5 regulatory axis that functions in stroke. In this work, young (8–12 weeks) male pep boy (PB), IRF4 or IRF5 flox, and IRF4 or IRF5 conditional knockout (CKO) mice were used to generate 8 types of bone marrow chimeras, to differentiate the role of central (PB-to-IRF CKO) vs. peripheral (IRF CKO-to-PB) phagocytic IRF4-IRF5 axis in stroke. Chimeras generated from PB and flox mice were used as controls. All chimeras were subjected to 60-min middle cerebral artery occlusion (MCAO) model. Three days after the stroke, outcomes and inflammatory responses were analyzed. We found that PB-to-IRF4 CKO chimeras had more robust microglial pro-inflammatory responses than IRF4 CKO-to-PB chimeras, while ameliorated microglial response was seen in PB-to-IRF5 CKO vs. IRF5 CKO-to-PB chimeras. PB-to-IRF4 or IRF5 CKO chimeras had worse or better stroke outcomes respectively than their controls, whereas IRF4 or 5 CKO-to-PB chimeras had similar outcomes compared to controls. We conclude that the central IRF4/5 signaling is responsible for microglial activation and mediates stroke outcomes.