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Abstract
Keratinocyte migration is fundamental to re-epithelialization and the restoration of epithelial barrier integrity in the skin and oral mucosa, though it is highly susceptible to impairment by the bacterial inflammatory mediator lipopolysaccharide (LPS). We demonstrate that LPS-activated toll-like receptor 4 (TLR4) interacts directly with the focal adhesion scaffold paxillin to induce site-specific phosphorylation at Ser273. This signaling event promotes persistent Rac1 activation, which disrupts the adhesion turnover essential for coordinated migration. Functional validation using Ser273 paxillin mutants demonstrated that this site-specific phosphorylation is necessary and sufficient to drive migratory dysfunction. Furthermore, pharmacologic Rac1 inhibition suppresses paxillin phosphorylation and restores epithelial organization, revealing a bidirectional relationship between paxillin and Rac1 signaling. These findings define a TLR4-paxillin-Rac1 signaling axis that links inflammatory activation to focal adhesion remodeling, identifying Rac1-dependent adhesion dysregulation as a mechanistic driver of impaired epithelial repair.