Myeloid Fbxw7 Prevents Pulmonary Fibrosis by Suppressing TGF-β Production

Abstract

Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by an inexorable decline in lung function with limited treatment options. The abnormal expression of transforming growth factor-β (TGF-β) in profibrotic macrophages is linked to severe pulmonary fibrosis, but the regulation mechanisms of TGF-β expression are incompletely understood. We found that decreased expression of E3 ubiquitin ligase Fbxw7 in peripheral blood mononuclear cells (PBMCs) was significantly related to the severity of pulmonary fibrosis in IPF patients. Fbxw7 is identified to be a crucial suppressing factor for pulmonary fibrosis development and progression in a mouse model induced by intratracheal bleomycin treatment. Myeloid cell-specific Fbxw7 deletion increases pulmonary monocyte-macrophages accumulation in lung tissue, and eventually promotes bleomycin-induced collagen deposition and progressive pulmonary fibrosis. Notably, the expression of TGF-β in profibrotic macrophages was significantly upregulated in myeloid cell-specific Fbxw7 deletion mice after bleomycin treatment. C-Jun has long been regarded as a critical transcription factor of Tgfb1, we clarified that Fbxw7 inhibits the expression of TGF-β in profibrotic macrophages by interacting with c-Jun and mediating its K48-linked ubiquitination and degradation. These findings provide insight into the role of Fbxw7 in the regulation of macrophages during the pathogenesis of pulmonary fibrosis.

Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast–Myofibroblast Transformation against Pulmonary Fibrosis

“…In PF, FBW7 promotes senescence through the ubiquitination of TPP1 in pulmonary epithelial cells, thereby aggravating PF, 44 while in macrophages, FBW7 inhibits TGFβ production by increasing ubiquitination of c-Jun to alleviate PF. 45 Thus, the regulation of CRL1 in PF has substrate specificity. Many substrates of CRL1 that have been reported in other diseases were believed to regulate fibroblast function, for example, SMAD4 in the TGFβ pathway; PFKFB3 in metabolic regulation; Nrf2 in oxidative stress; Bcl2 family in cell survival regulation; and Akt1, JAK3, and mTOR in classical signal pathways.…”

“…CRL1 has a large number of substrates and regulates various cell functions. In PF, FBW7 promotes senescence through the ubiquitination of TPP1 in pulmonary epithelial cells, thereby aggravating PF, while in macrophages, FBW7 inhibits TGFβ production by increasing ubiquitination of c-Jun to alleviate PF . Thus, the regulation of CRL1 in PF has substrate specificity.…”

Therapeutic Effect of Astragali Radix Extract Injection Combined with Bone Marrow Mesenchymal Stem Cells in Bleomycin-Induced Pulmonary Fibrotic Rats

“…It has the subtypes TGF- β 1, TGF- β 2, and TGF- β 3, of which TGF- β 1 is most closely associated with fibrotic disease [ 46 ]. On the one hand, TGF- β 1 regulates the Smad pathway and recruits circulating fibroblasts to the lungs while promoting epithelial- and endothelial-mesenchymal transitions, intrapulmonary fibroblast proliferation, and extracellular matrix deposition [ 47 ]. On the other hand, TGF- β 1 can induce macrophage recruitment, activate signaling pathways such as JNK, p38, and ERK, produce various inflammatory factors such as IL-1 β , and aggravate inflammatory injury.…”

Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy

“…In the study of Zhang et al, FBXW7 inhibited by calcium/ calmodulin-dependent protein kinase IV (CaMKIV) promoted the upregulation of mTOR in macrophages, resulting in the LPS-induced autophagy of macrophages subsequently (152). FBXW7 deficiency in myeloid cells promotes the recruitment of monocyte-macrophages in pulmonary tissue, facilitating the collagen deposition induced by bleomycin and finally developing into progressive pulmonary fibrosis (153). Moreover, the suppression of MCL-1 by FBXW7 in M2 macrophages demonstrated an improved apoptosis and repressed EMT phenotype of colon cancer cells (8).…”