The role of microglial/macrophagic salt-inducible kinase 3 on normal and excessive phagocytosis after transient focal cerebral ischemia

• DOI: 10.1007/s00018-022-04465-1
• Publication Date: 2022-07-21T22:02:23Z
• Authors: Ke Wang; Chenran Wang; Di Chen; Yichen Huang; Jiaying Li; Pengju Wei; Ziyu Shi; Yue Zhang; Yanqin Gao
• Keywords: Conditional gene knockout

Previous studies suggested that anti-inflammatory microglia/macrophages (Mi/MΦ) play a role in "normal phagocytosis," which promoted the rapid clearance of necrotic substances and apoptotic cells. More recently, few have found Mi/MΦ also "pathological phagocytosis" form excessive or reduced phagocytosis, thereby worsening damage induced by CNS diseases. However, underlying mechanisms subtypes related to this pathological phagocytosis are still unknown. Salt-inducible kinase 3 (SIK3), member 5' adenosine monophosphate-activated protein (AMPK) family, has been shown regulate inflammation several peripheral Whether SIK3 regulates inflammatory response diseases is currently Therefore, study, we created transgenic tamoxifen-induced Mi/MΦ-specific conditional knockout (SIK3-cKO) mouse examine SIK3's phagocytotic function transient focal cerebral ischemia (tFCI). By single-cell RNA-seq, pro-inflammatory phenotype performed an function, but normal function. We SIK3-cKO caused heterogenization from transitional after tFCI. This phenotypic shift corresponded with enhanced both live neurons. Interestingly, myelin debris attenuating non-damaged sheath, protecting white matter integrity CD16, pro-inflammation marker, was decreased significantly correlated "excessive phagocytosis." long-term recovery neurological as assessed electrophysiological compound action potential (CAPs) behavioral analysis. study first show diseases, reveals promoting inhibits cells facilitates inhibition may be therapeutic target stroke other accompanying destruction. In acute stage tFCI, polarized into different phenotypes. The contrast, After Mi/MΦ. (normal phagocytosis) living neuronal cell bodies (excessive gray matter. specifically increased concurrent attenuation sheath These changes were associated protection neurofunctional