From Tim4 to ischemic stroke: a mitochondrial pathway driving microglial M1 polarization

Abstract

Microglia dysfunction is a critical contributor in ischemic stroke, where T-cell immunoglobulin and mucin domain 4 (Tim4) may play a significant role. After ischemic stroke modeling with the middle cerebral artery occlusion (MCAO) method, the changes in infarct volume, neurological deficits, cell apoptosis, microglial polarization, Tim4, mitochondrial fission proteins, mitochondrial membrane potential (MMP), and regulation of reactive oxygen species (ROS) were detected. In oxygen-glucose deprivation (OGD) model, the effects of Tim4 on microglial phenotypes, mitochondrial fission proteins, inflammatory factors, and MMP were evaluated. MCAO increased brain infarct volume, neurological deficits, apoptosis, and the proportion of M1-type microglia. In the OGD model, there was a drop in M2 microglia and a rise in M1 microglia, as well as upregulated tumor necrosis factor-alp (TNF-α) and Interleukin-1 beta (IL-1β). Upregulation of Tim4 was associated with increased levels of ROS in microglia, enhanced expressions of mitochondrial fission factor (MFF) and dynamin-related protein 1 (Drp1), and reduced MMP, which can be reversed by knocking down Tim4 expression. This implied that Tim4 could promote M1 microglial polarization and mitochondrial dynamics. However, Drp1 overexpression offset the effects of Tim4 knockdown on microglial polarization. In conclusion, Tim4 regulates the M1 microglial polarization via mitochondria, serving as a potential therapeutic target for ischemic stroke.

Keywords: Ischemic stroke; M1 polarization; Microglia; Mitochondria; T-cell immunoglobulin and mucin domain 4.