Inflammation drives TGFβ1 activation via the αvβ6 integrin-mechanotransduction pathway in human skin

Transforming growth factor β (TGFβ) is a critical regulator of skin homeostasis and inflammation, including psoriasis. Multiple mechanisms can regulate TGFβ signaling, such as the activation of latent TGFβ1 through integrin-dependent pathways. We investigated the molecular mechanisms of TGFβ1 activation during cutaneous inflammation using reconstructed human epidermis treated with inflammatory cytokine cocktail. We report αvβ6 integrin upregulation and enhanced binding of TGFβ1 latency-associated peptide (LAP), which, however, did not result in active TGFβ1 release, restricting the TGFβ1 activation to paracrine signaling in keratinocytes. Further, we identify a mechanosensitive positive feedback loop, that occurs downstream of inflammatory stimuli and involves TGFβ-mediated activation of mechanotransduction, further promoting mechanodependent, αvβ6-mediated TGFβ1 activation in keratinocytes. Thus, we reveal a mechanism of inflammation-driven TGFβ1 signaling regulation in human epidermis, linking cell mechanobiology to immunological outcomes, suggesting new therapeutic avenues.