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

This study investigates how inflammatory cues regulate TGFβ1 signaling in human epidermis by coupling immune stimulation to mechanotransduction-dependent latent TGFβ1 activation. Using human psoriatic skin biopsies and an in vitro reconstructed human epidermis (RHE) model stimulated with a psoriasis-relevant cytokine cocktail (M5), the authors show that inflammation upregulates integrin αvβ6 in keratinocytes and increases binding/handling of latent TGFβ1 complexes (LAP/TGFβ1). Despite enhanced LAP binding, inflammatory stimulation did not increase free active TGFβ1 release into the extracellular medium; instead, the data support a model where αvβ6 promotes internalization/uptake of latent complexes and restricts signaling largely to keratinocyte paracrine/autocrine effects. Mechanistically, the work demonstrates that αvβ6-dependent latent TGFβ1 activation is force-dependent: inhibiting actomyosin contractility (blebbistatin) suppresses inflammation-induced LAP binding, while externally applied mechanical stretch increases LAP binding. The study further identifies a positive feedback loop in which TGFβ1 signaling enhances mechanotransduction (e.g., increased myosin light chain phosphorylation, focal adhesion changes, YAP signaling), which in turn promotes additional αvβ6-mediated TGFβ1 activation under inflammatory conditions. Overall, the findings connect epidermal inflammation, integrin-mediated latent TGFβ1 handling, and mechanotransduction into a reinforcing circuit relevant to psoriasis pathogenesis and potential therapeutic targeting of αvβ6/mechanosignaling.