JAK2/STAT3 Axis Intermediates Microglia/Macrophage Polarization During Cerebral Ischemia/Reperfusion Injury

Subtypes of microglia/macrophage regulate the inflammation in the opposite direction during ischemic stroke. JAK2/STAT3 signaling pathway participates in the development of stroke-related inflammation via ischemic stimulation. However, the relationship between JAK2/STAT3 pathway and microglia/macrophage phenotype transformation is unclear.This study established a transient middle cerebral artery occlusion (tMCAO) model in male STAT3f/f and STAT3f/f LysMcre+ mice and evaluated the neurological deficit on the 3rd day using Longa score. The brains were stained by TTC to determine the infarction volume. Western blotting and QPCR were used to determine the expression of JAK2/STAT3 pathway and microglia/macrophage-related markers. Immunofluorescence staining was used to detect the levels of polarization-related indexes. QPCR also assessed the effect of STAT3 knockout on inflammatory factors in the infarction. Moreover, established the OGD/R model using BV2 cells to further verify the role of STAT3 on microglia/macrophage polarization.For the conditioned STAT3-KO mice, the infarction was significantly increased after MCAO, accompanied by the aggravation of neurological deficit. Higher expression of iNOS and CD16/32 than Arg-1, Ym-1, and CD206 in vivo and in vitro, and decreased p-STAT3/STAT3 ratio in STAT3f/f LysMcre+ mice, while the p-JAK2/JAK2 ratio increased. In addition, increased M1/M2 ratio and elevated expression of IL-1β, IL-6, TNF-α with STAT3 deletion, as well as increased CD68+/iNOS+ cell numbers.Collectively, these results reveal that JAK2/STAT3 signaling pathway regulates the microglia/macrophage polarization (skewing toward the M2 polarization) during the CIRI, thus alleviating brain damage. Therefore, approaches targeting JAK2/STAT3 activation are promising therapies for ischemic stroke.