期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.633796
关键词
TREM2; CSF1R; interaction; cell survival; microglia
类别
资金
- National Natural Science Foundation of China [81771164, 91949129, 81771377, 92049202, U1705285]
- Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University [SKLCSB2019KF014]
- Natural Science Foundation of Fujian Province of China [2018D0022, 2020J01014]
TREM2 and CSF1R interact directly in microglia cells, modulating their expression levels. Administration of CSF1 partially restores the survival ability of Trem2-deficient microglia, showing potential therapeutic intervention in TREM2 variant-bearing patients with a high risk of Alzheimer's disease.
Triggering receptor expressed on myeloid cells-2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) are crucial molecules for microgliopathy, which is characterized by microglia dysfunction and has recently been proposed as the neuropathological hallmark of neurological disorders. TREM2 and CSF1R are receptors expressed primarily in microglia in the brain and modulate microglial activation and survival. They are thought to be in close physical proximity. However, whether there is a direct interaction between these receptors remains elusive. Moreover, the physiological role and mechanism of the interaction of TREM2 and CSF1R remain to be determined. Here, we found that TREM2 interacted with CSF1R based on a co-immunoprecipitation assay. Additionally, we found that CSF1R knockdown significantly reduced the survival of primary microglia and increased the Trem2 mRNA level. In contrast, CSF1R expression was increased in Trem2-deficient microglia. Interestingly, administration of CSF1, the ligand of CSF1R, partially restored the survival of Trem2-deficient microglia in vitro and in vivo. Furthermore, CSF1 ameliorated A beta plaques deposition in Trem2(-/-); 5XFAD mouse brain. These findings provide solid evidence that TREM2 and CSF1R have intrinsic abilities to form complexes and mutually modulate their expression. These findings also indicate the potential role of CSF1 in therapeutic intervention in TREM2 variant-bearing patients with a high risk of Alzheimer's disease (AD).
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