期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.757231
关键词
E3 ubiquitin ligase; dendritic cell (DC); FLT3; liver inflammation; homeostasis
类别
资金
- A. Aisenstadt Chair Fund
- Chinese Scholarship Council
- National Natural Science Foundation of China [31270939, 81471526, 81771667]
- Training Program of the Major Research Plan in regional immunology of the National Natural Science Foundation of China [91442110]
- PCSIRT [IRT1075]
- National Health and Medical Research Concil project [1101318]
- Medical and Health Infrastructure Fund
- NSHLIJ Institutional Fund
DC-specific ablation of CBL and CBL-B leads to spontaneous liver inflammation and fibrosis in mice, associated with an increase in cDC1s and abnormal activation of the FLT3-mTOR signaling pathway. This study highlights the critical role of CBLs in maintaining DC homeostasis and immune quiescence, and suggests their relevance to liver inflammatory diseases and fibrosis in humans.
Dendritic cells (DCs) are composed of multiple lineages of hematopoietic cells and orchestrate immune responses upon detecting the danger and inflammatory signals associated with pathogen and damaged tissues. Under steady-state, DCs are maintained at limited numbers and the functionally quiescent status. While it is known that a fine balance in the DC homeostasis and activation status is also important to prevent autoimmune diseases and hyperinflammation, mechanisms that control DC development and activation under stead-state remain not fully understood. Here we show that DC-specific ablation of CBL and CBL-B (CBL-/-CBL-B-/-) leads to spontaneous liver inflammation and fibrosis and early death of the mice. The mutant mice have a marked expansion of classic CD8 alpha(+)/CD103(+) DCs (cDC1s) in peripheral lymphoid organs and the liver. These DCs exhibit atypical activation phenotypes characterized by an increased production of inflammatory cytokines and chemokines but not the cell surface MHC-II and costimulatory ligands. While the mutant mice also have massive T cell activation, lymphocytes are not required for the disease development. The CBL-/-CBL-B-/- mutation enhances FLT3-mTOR signaling, due to defective FLT3 ubiquitination and degradation. Blockade of FLT3-mTOR signaling normalizes the homeostasis of cDC1s and attenuates liver inflammation. Our result thus reveals a critical role of CBLs in the maintenance of DC homeostasis and immune quiescence. This regulation could be relevant to liver inflammatory diseases and fibrosis in humans.
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