TRPA1 as a potential factor and drug target in scleroderma: dermal fibrosis and alternative macrophage activation are attenuated in TRPA1-deficient mice in bleomycin-induced experimental model of scleroderma

Abstract

Background Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. Methods Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. Results Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. Conclusions In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.

Discovery of PRDM16‐Mediated TRPA1 Induction as the Mechanism for Low Tubulo‐Interstitial Fibrosis in Diabetic Kidney Disease

“…On the contrary, knockout of TRPA1 increased age‐related cardiac fibrosis, intestinal fibrosis in experimental Crohn's disease, and bleomycin‐induced dermal fibrosis. [ 19,31,32 ] Our present study reports the first evidence for the involvement of TRPA1 in renal fibrosis. Especially, knockdown of TRPA1 enhanced TGF‐β1 expression and renal interstitial fibrosis in db/db diabetic mice, whereas overexpression of TRPA1 had opposite effects (Figures 4 and 5).…”

Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets

“…Mice lacking TRPA1 displayed reduced dermal thickening, diminished collagen accumulation, and decreased expression of pro-fibrotic factors. Blocking TRPA1 potentially relieves conditions such as systemic sclerosis and scleroderma ( Maki-Opas et al, 2023 ). IBD is often associated with disruption of mucosal integrity.…”