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

## TL;DR

Inflammation in human skin activates TGFβ1 through the αvβ6 integrin pathway, but the effect is limited to nearby cells and involves a mechanical feedback loop.

## Contribution

The study reveals a mechanosensitive feedback loop linking inflammation, TGFβ1 activation, and keratinocyte signaling in human skin.

## Key findings

- Inflammation increases αvβ6 integrin and TGFβ1 latency-associated peptide binding.
- TGFβ1 activation remains paracrine in psoriatic keratinocytes.
- A mechanodependent feedback loop enhances TGFβ1 signaling in the epidermis.

## Abstract

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.

•Inflammation promotes αvβ6 integrin-dependent TGFβ1 activation by keratinocytes•TGFβ1 activation remains confined to paracrine effects in psoriatic keratinocytes•Mechanodependent feedback loop drives TGFβ1 activation and signaling in epidermis

Inflammation promotes αvβ6 integrin-dependent TGFβ1 activation by keratinocytes

TGFβ1 activation remains confined to paracrine effects in psoriatic keratinocytes

Mechanodependent feedback loop drives TGFβ1 activation and signaling in epidermis

Mechanobiology; Immunology; Cell biology