ATAT1 deficiency enhances microglia/macrophage-mediated erythrophagocytosis and hematoma absorption following intracerebral hemorrhage.

Abstract

MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage. Dynamic cytoskeletal changes accompany phagocytosis. However, whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear. In this study, we investigated the function of acetylated α-tubulin, a stabilized microtubule form, in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo. We first assessed the function of acetylated α-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines. Acetylated α-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis. Moreover, silencing α-tubulin acetyltransferase 1 (ATAT1), a newly discovered α-tubulin acetyltransferase, decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells. Consistent with these findings, in ATAT1-/- mice, we observed increased ionized calcium binding adapter molecule 1 (Iba1) and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage. Additionally, knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma, ultimately improving neurological recovery of mice after intracerebral hemorrhage. These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage. These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.