Integrin α4β1 is required for IL‐1α‐ and Nrf2‐dependent, Cox‐2 induction in fibroblasts, supporting a mechanism that suppresses α‐SMA expression

Growth and repair processes, both normal and pathological, require reciprocal interactions between cells and their microenvironment. Integrins are bidirectional, cell surface receptors that transduce mechanical and chemical signals to and from the extracellular matrix. We recently reported that keratinocyte α3β1 is required for interleukin (IL)‐1α secretion. Importantly, IL‐1α regulates fibroblast Cox‐2 expression and prostaglandin E2 (PGE 2 ) secretion, thereby linking keratinocyte integrin function to a paracrine signal that suppresses the myofibroblast phenotype. We now report that fibroblast integrin α4β1 is required for this IL‐1α‐induced, Cox‐2 expression. Moreover, Cox‐2 induction by IL‐1α requires Nuclear factor erythroid 2‐related factor 2 (Nrf2), the master regulator of redox homeostasis; and integrin α4β1 is necessary to maintain IL‐1α‐dependent, Nrf2 levels. Treating fibroblasts with a Nrf‐2 activating compound inhibits TGF‐β‐dependent, alpha smooth muscle actin (α‐SMA) expression and stress fibre formation. Our data suggest that fibroblast integrin α4β1 regulates—depending on microenvironmental cues—the differentiated state of fibroblasts through a signalling network in which IL‐1α, Cox‐2 and Nrf2 participate.