GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression.

Fibrosis is characterized by excessive deposition of extracellular matrix proteins, particularly collagen, caused by myofibroblasts in response to chronic inflammation. Although G protein-coupled receptors (GPCRs) are among the targets of current antifibrotic drugs, no drug has yet been approved to stop fibrosis progression. Herein, we aimed to identify GPCRs with profibrotic effects. In gene expression analysis of mouse lungs with induced fibrosis, eight GPCRs were identified, showing a >2-fold increase in mRNA expression after fibrosis induction. Among them, we focused on Gpr176 owing to its significant correlation with a myofibroblast marker α-smooth muscle actin (αSMA), the profibrotic factor transforming growth factor ß1 (TGFß1), and collagen in a human lung gene expression database. Similar to the lung fibrosis model, increased Gpr176 expression was also observed in other organs affected by fibrosis, including the kidney, liver, and heart, suggesting its role in fibrosis across various organs. Furthermore, fibroblasts abundantly expressed Gpr176 compared to alveolar epithelial cells, endothelial cells, and macrophages in the fibrotic lung. GPR176 expression was unaffected by TGFß1 stimulation in rat renal fibroblast NRK-49 cells, whereas knockdown of Gpr176 by siRNA reduced TGFß1-induced expression of αSMA, fibronectin, and collagen as well as Smad2 phosphorylation. This suggested that Gpr176 regulates fibroblast activation. Consequently, Gpr176 acts in a profibrotic manner, and inhibiting its activity could potentially prevent myofibroblast differentiation and improve fibrosis. Developing a GPR176 inverse agonist or allosteric modulator is a promising therapeutic approach for fibrosis.

Sweat Protects against Contact Hypersensitivity: Transient Sweat Suppression Compromises Skin Barrier Function in Mice.

Although subtle barrier defects may facilitate allergen penetration, thereby enabling allergic sensitization, the relationship between sweating disturbance and skin barrier function is unknown. However, many studies on contact hypersensitivity in mice examined ear skin, which does not sweat, instead of the footpad, where sweating is uniquely present. In this study, we assessed whether sweat suppression in the footpad before hapten application provoked a skin barrier abnormality and reduced inflammatory thresholds to topical haptens. Mice without any genetic skin barrier dysfunction displayed markedly reduced inflammatory thresholds to haptens under transient sweat suppression before hapten application. Epicutaneously applied haptens penetrated the skin more robustly in the presence of sweat suppression compared with that in its absence, although this increase was abolished by exposure to high-humidity conditions. These mice displayed a subtle atopic dermatitis-like inflammation mediated by type 2 response-dominant inflammation and increased IgE responses, mimicking some events occurring in nonlesional atopic dermatitis skin in humans and in murine models. These lesions were dramatically attenuated by exposure to high-humidity conditions. In our model, hapten sensitization does not require mechanical injury, explaining why sensitization occurs through nonlesional atopic dermatitis skin. Awareness of the importance of preserving sweating responses is essential to prevent occupational contact dermatitis and atopic dermatitis.