Lamin A/C mediates microglial activation by modulating cell proliferation and immune response

• Published in: Journal of neuroscience research 2024-01, Vol.102 (1), p.e25263-n/a
• Main Authors: Liu, Haotian, Liu, Xinnan, Luo, Shiqi, Ma, Rayna, Ge, Wei, Meng, Shu, Gao, Yanpan
• Format: Article
• Language: English
• Subjects: Aging; Biological activity; Brain; Cell activation; Cell growth; Cell lines; Cell proliferation; Chromatin; Cytology; DNA biosynthesis; Immune response; Immune system; Inflammation; Lamin A/C; Macrophages; Mechanotransduction; Microglia; mRNA; mRNA processing; Phagocytosis; Progeria; Proteins; Proteomes; Proteomics; Stat1 protein
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.25263

Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna−/− mice, primary microglia, Lmna knockout (Lmna‐KO) and Lmna‐knockdown (Lmna‐KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL‐1β, IL‐6, and TNF‐α), were significantly suppressed in all Lamin A/C‐deficient models when stimulated with LPS. TMT‐based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C‐regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna−/− microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune‐ and proliferation‐related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C‐mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C. The Lamin A/C is a major regulator for microglia activation by modulating immune‐ and proliferation‐related biological processes. The attenuated inflammatory response caused by Lamin A/C deletion protects the brain of progeria patients from inflammatory brain damage.