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bioRxiv · 10.1101/2022.04.12.488008

An Inhibitory Function of TRPA1 Channels in TGF-β1-driven Fibroblast to Myofibroblast Differentiation

Geiger, F.·Zeitlmayr, S.·Staab-Weijnitz, C. A.·Rajan, S.·Breit, A.·Gudermann, T.·Dietrich, A.
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Abstract

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective Ca2+ permeable cation channel, which was originally cloned from human lung fibroblasts (HLFs). TRPA1-mediated Ca2+ entry is evoked by exposure to several chemicals, including allyl isothiocyanate (AITC), and a protective effect of TRPA1 activation in the development of cardiac fibrosis has been proposed. Yet, the function of TRPA1 in transforming growth factor {beta}1 (TGF-{beta}1)-driven fibroblast to myofibroblast differentiation and the development of pulmonary fibrosis remains elusive. TRPA1 expression and function was analyzed in cultured primary HLFs, and mRNA levels were significantly reduced after adding TGF-{beta}1. Expression of genes encoding fibrosis markers, e.g. alpha smooth muscle actin (ACTA2), plasminogen activator inhibitor 1 (SERPINE1), fibronectin (FN1) and type I collagen (COL1A1) was increased after siRNA-mediated down-regulation of TRPA1-mRNA in HLFs. Moreover, AITC-induced Ca2+ entry in HLFs was decreased after TGF-{beta}1 treatment and by application of TRPA1 siRNAs, while AITC treatment alone did not reduce cell viability or enhanced apoptosis. Cell barrier function increased after addition of TRPA1 siRNAs or TGF-{beta}1 treatment. Most interestingly, AITC-induced TRPA1 activation augmented ERK1/2 phosphorylation, which might inhibit TGF-{beta}-receptor signaling. Our results suggest an inhibitory function of TRPA1 channels in TGF-{beta}1-driven fibroblast to myofibroblast differentiation. Therefore, activation of TRPA1 channels might be protective during the development of pulmonary fibrosis in patients.

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Geiger, F., Zeitlmayr, S., Staab-Weijnitz, C. A., Rajan, S., Breit, A., Gudermann, T., Dietrich, A.. 2022-04-12. An Inhibitory Function of TRPA1 Channels in TGF-β1-driven Fibroblast to Myofibroblast Differentiation. https://doi.org/10.1101/2022.04.12.488008

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