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

Abstract

The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in dendritic cells (DCs) remains unclear. To investigate the role of Cbl family members in DCs, we created dendritic cell double-deficient Casitas B lymphoma-b (Cbl-b) and Casitas B lineage lymphoma (c-Cbl) mice by crossing Cbl-b−/− mice with c-Cblflox/flox CD11c-Cre+ mice. We found that specific deletion of Cbl-b and c-Cbl in CD11c+ cells, predominantly in DCs, led to liver fibrosis, cirrhosis, and accumulation of systemic conventional Type I DCs (cDC1s) due to enhanced cell proliferation and decreased cell apoptosis. In addition to a change in DC number, double knockout (dKO) cDC1s exhibited a partially activated status as indicated by high basal expression levels of certain cytokines and possessed an enhanced capacity to prime T cells. After adoptive transfer, dKO cDC1s could drive liver fibrosis too. In further experiments, we demonstrated that Cbl-b and c-Cbl could target signal transducer and activator of transcription 5 (STAT5), a transcriptional repressor for the pro-apoptotic protein Bim, to promote ubiquitination-mediated degradation and cell apoptosis in cDC1s. Further extensive experiments revealed that Cbl-b mediated K27-linked ubiquitination of lysine 164 of STAT5a while c-Cbl induced K29-linked ubiquitination of lysine 696 of STAT5a and K27-linked ubiquitination of lysine 140 and 694 of STAT5b. Thus, our findings indicate a functional redundancy of Cbl-b and c-Cbl in cDC homeostasis and maturation.

The ubiquitin ligases Cbl and Cbl-b regulate macrophage growth by controlling CSF-1R import into macropinosomes

“…Our findings reproduce some of these phenotypes, however these are mild when compared with the phenotype of DKO macrophages, leading to the conclusion that either Cbl or Cbl-b protein is sufficient to regulate CSF-1-depndent macrophage growth and that their overlapping functions protect against sustained proliferation of myeloid cells, which is also consistent with the myeloproliferative phenotype observed in the DKO mice. Moreover, Cbl and Cbl-b were recently found to also constrain the growth of type 1 conventional dendritic cells (Xu et al. , 2022 ).…”

“…Together, these shape the signaling and transcriptional regulation of the CSF-1R and constrain macrophage proliferation. Thus, Cbl and Cbl-b play a critical role in controlling CSF-1R signaling and macrophage-related growth and likely contribute to the regulation of other myeloid growth factor receptors, potentially including the GM-CSF receptor ( Xu et al. , 2022 ).…”

Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells

“…Elevated Xcr1cDC1 was observed in the NASH model to increase pro-inflammatory CD8T cells and exacerbated NASH to cirrhosis ( 100 ). The deficiency of Cbl-b and c-Cbl in DCs led to the excessive accumulation of cDC1 in the liver and promoted liver cirrhosis and premature death in mice ( 101 ). The Wnt/β-catenin pathway is crucial in liver homeostasis ( 102 ).…”