Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling

Abstract

Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood1. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK)1,2. Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders3–5. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK–ERK–MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.

Force generation and transmission in keloid fibroblasts: dissecting the role of mechanosensitive molecules in cell function

“…This is relevant also in vivo as the skin-specific deletion of FAK impairs load-induced matrix formation in a mouse model of hypertrophic scarring (6). Taken together, these findings confirm that coupling of intracellular and extracellular cues via mechanosensitive molecules like FAK is relevant for cell migration during wound healing (Fig.…”

Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix

“…In addition, MYO1E protects kidney podocytes from mechanical stressinduced injury, as does SPP1, which may be induced by FAK (33,34). Moreover, keloid formation (i.e., a wound-healing reaction with excessive scar formation) has been associated with MYO1E (35) and FAK function (36). MYO1E/FAK-induced SPP1 may play a role in keloid formation because SPP1 is known to drive tissue fibrosis (37).…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Moreover, a recent in vivo wound healing study linked mechanical forces to inflammatory activation of fibroblasts via focal adhesion kinase (FAK), a transducer of both inflammatory and physical signals: In a mouse model of hypertrophic scar formation, fibroblast-specific knockdown of FAK resulted in reduced inflammation and fibrosis, compared with control mice [50]. While not involving cancer, these studies indicate that changes in tissue architecture as a result of aberrant epithelial proliferation, an early neoplastic response, may result in activation of inflammatory signalling by stromal fibroblasts, a hypothesis supported by reports of inflammatory signalling by stromal fibroblasts in benign prostatic hyperplasia [50][51][52][53]. Taken together, it is reasonable to hypothesize that biomechanical forces applied by aberrant proliferation of transformed epithelial cells in incipient tumours may be one of the physiological signals that trigger pro-inflammatory signalling in resident tissue fibroblasts.…”