PMID- 34630435 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220314 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Ubiquitin Ligases CBL and CBL-B Maintain the Homeostasis and Immune Quiescence of Dendritic Cells. PG - 757231 LID - 10.3389/fimmu.2021.757231 [doi] LID - 757231 AB - 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 CD8alpha(+)/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. CI - Copyright (c) 2021 Tong, Li, Zhang, Gong, Sun, Calderon, Zhang, Li, Gadzinski, Langdon, Reizis, Zou and Gu. FAU - Tong, Haijun AU - Tong H AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. AD - Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada. AD - Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada. FAU - Li, Xin AU - Li X AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. AD - Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada. AD - Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada. FAU - Zhang, Jinping AU - Zhang J AD - Institute of Biology and Medical Science, SooChow University, Jiangsu, China. FAU - Gong, Liying AU - Gong L AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. AD - Division of Experimental Medicine, McGill University, Montreal, QC, Canada. FAU - Sun, Weili AU - Sun W AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. AD - Division of Experimental Medicine, McGill University, Montreal, QC, Canada. FAU - Calderon, Virginie AU - Calderon V AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. FAU - Zhang, Xiaochen AU - Zhang X AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. FAU - Li, Yue AU - Li Y AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. FAU - Gadzinski, Adeline AU - Gadzinski A AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. FAU - Langdon, Wallace Y AU - Langdon WY AD - School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia. FAU - Reizis, Boris AU - Reizis B AD - Department of Pathology, New York University Langone Medical Center, New York, NY, United States. AD - Department of Medicine, New York University Langone Medical Center, New York, NY, United States. FAU - Zou, Yongrui AU - Zou Y AD - The Feinstein Institute for Medical Research, Manhasset, New York, NY, United States. FAU - Gu, Hua AU - Gu H AD - Molecular Immunology Research Unit, Montreal Clinic Research Institute, Montreal, QC, Canada. AD - Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada. AD - Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada. AD - Division of Experimental Medicine, McGill University, Montreal, QC, Canada. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210923 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Cblb protein, mouse) RN - 0 (Cytokines) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl) RN - EC 2.7.10.1 (Flt3 protein, mouse) RN - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 6.3.2.- (Cbl protein, mouse) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adaptor Proteins, Signal Transducing/deficiency/genetics/*physiology MH - Animals MH - Antigen Presentation MH - Cell Division MH - Cells, Cultured MH - Cytokines/metabolism MH - Dendritic Cells/cytology/*immunology/metabolism MH - Hepatitis, Autoimmune/genetics/immunology MH - Homeostasis MH - Lymphocyte Subsets/immunology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Point Mutation MH - Proto-Oncogene Proteins c-akt/physiology MH - Proto-Oncogene Proteins c-cbl/deficiency/genetics/*physiology MH - Sirolimus/pharmacology MH - fms-Like Tyrosine Kinase 3/physiology PMC - PMC8494778 OTO - NOTNLM OT - E3 ubiquitin ligase OT - FLT3 OT - dendritic cell (DC) OT - homeostasis OT - liver inflammation COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/10/12 06:00 MHDA- 2022/03/15 06:00 PMCR- 2021/01/01 CRDT- 2021/10/11 05:55 PHST- 2021/08/11 00:00 [received] PHST- 2021/09/06 00:00 [accepted] PHST- 2021/10/11 05:55 [entrez] PHST- 2021/10/12 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.757231 [doi] PST - epublish SO - Front Immunol. 2021 Sep 23;12:757231. doi: 10.3389/fimmu.2021.757231. eCollection 2021.