Ubiquitin Ligases CBL and CBL-B Maintain the Homeostasis and Immune Quiescence of Dendritic Cells

Abstract

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 CD8α+/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.

Ablation of Cbl-b and c-Cbl in dendritic cells causes spontaneous liver cirrhosis via altering multiple properties of CD103+ cDC1s

“…Liver fibrosis in dKO mice was autoimmune-unrelated as dKO mice did not manifest autoimmune disorders, which was also confirmed by data using Rag1 −/− dKO mice model [ 36 ]. Although macrophages and NK cells are involved in liver fibrosis, we did not observe an increase in the numbers of liver infiltrating NK cells and macrophages [ 36 ].…”

“…Liver fibrosis in dKO mice was autoimmune-unrelated as dKO mice did not manifest autoimmune disorders, which was also confirmed by data using Rag1 −/− dKO mice model [ 36 ]. Although macrophages and NK cells are involved in liver fibrosis, we did not observe an increase in the numbers of liver infiltrating NK cells and macrophages [ 36 ]. Adoptive transfer result indicated that dKO cDC1s could directly initiate or drive liver fibrosis, possibly by creating an inflammatory environment due to their massive hepatic accumulation and elevated basal expression of inflammatory cytokines.…”

Integrated Bioinformatics Analysis for Revealing CBL is a Potential Diagnosing Biomarker and Related Immune Infiltration in Parkinson’s Disease

“… 27 They regulate the development, tolerance, and function of T cells and B cells by modulating signals transmitted by T cell and B cell antigen receptors and co-receptors. 47 Studies have shown that c-Cbl inhibits microglia-mediated neuroinflammation by negatively regulating the PI3K/Akt/NF-κB pathway. 48 Microglia, as active contributors to neuronal damage in PD, play an important role in the inflammatory process caused by PD pathogenesis, and inhibiting microglial activation is considered a promising therapeutic strategy for the treatment of PD.…”