Macrophage-secreted TGF-β₁ contributes to fibroblast activation and ureteral stricture after ablation injury

Abstract

Iatrogenic injury to the healthy ureter during ureteroscope-guided ablation of malignant or nonmalignant disease can result in ureteral stricture. Transforming growth factor (TGF)-β1-mediated scar formation is considered to underlie ureteral stricture, but the cellular sources of this cytokine and the sequelae preceding iatrogenic stricture formation are unknown. Using a swine model of ureteral injury with irreversible electroporation (IRE), we evaluated the cellular sources of TGF-β1 and scar formation at the site of injury and examined in vitro whether the effects of TGF-β1 could be attenuated by pirfenidone. We observed that proliferation and α-smooth muscle actin expression by fibroblasts were restricted to injured tissue and coincided with proliferation of macrophages. Collagen deposition and scarring of the ureter were associated with increased TGF-β1 expression in both fibroblasts and macrophages. Using in vitro experiments, we demonstrated that macrophages stimulated by cells that were killed with IRE, but not LPS, secreted TGF-β1, consistent with a wound healing phenotype. Furthermore, using 3T3 fibroblasts, we demonstrated that stimulation with paracrine TGF-β1 is necessary and sufficient to promote differentiation of fibroblasts and increase collagen secretion. In vitro, we also showed that treatment with pirfenidone, which modulates TGF-β1 activity, limits proliferation and TGF-β1 secretion in macrophages and scar formation-related activity by fibroblasts. In conclusion, we identified wound healing-related macrophages to be an important source of TGF-β1 in the injured ureter, which may be a paracrine source of TGF-β1 driving scar formation by fibroblasts, resulting in stricture formation.

Cymbopogon winterianus Essential Oil Attenuates Bleomycin-Induced Pulmonary Fibrosis in a Murine Model

“…To prove this theory right, the immunohistochemical expression of TGF-β was assessed in histological sections of lungs with BLM-induced pulmonary fibrosis. As expected, untreated animals presented the greatest counts of TGF-β-expressing cells, which agrees with other studies previously reported [ 56 , 82 , 83 ]. The significant decrease in pulmonary cells expressing TGF-β in EOCW-treated groups at 100 and 200 mg/kg, as well as in the deflazacort-treated group, is fully supported by the analysis of α-SMA-positive cells, attesting to the close relation between this cytokine and myofibroblast differentiation.…”

“…Inflammatory cells and other epithelial and mesenchymal cells activated by inflammatory cytokines are the major sources of TGF-β. Therefore, drugs such as steroids and cyclooxygenase inhibitors have been considered effective in reducing inflammatory cytokines, such as TGF-β, and consequently attenuate collagen deposition [ 82 ].…”

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

“…M2 type TAMs can activate CAFs and thus help tumor progression (247). In addition, M2 macrophages can influence the MMT of fibroblasts, resulting in enhanced reactivity (238).…”

The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma

“…However, there are few reports that macrophages activate fibroblasts. Ueshima, et al [ 35 ] demonstrated that TGF-β1 secreted from macrophages promoted fibroblast differentiation and scar formation in the ureter. To the best of our knowledge, this study is the first to confirm the activation of CAFs by TAMs in the TME.…”