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

Author:

Liu Haotian12ORCID,Liu Xinnan2,Luo Shiqi2,Ma Rayna2,Ge Wei2,Meng Shu2,Gao Yanpan12

Affiliation:

1. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine Hangzhou City University Hangzhou China

2. Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College Beijing China

Abstract

AbstractLamin 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience

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