Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program.

Significance: Chronic inflammation and maladaptive repair contribute to the development of fibrosis that negatively impacts quality of life and organ function. The toll-like receptor (TLR) system is a critical node in the tissue response to both exogenous (pathogen-associated) and endogenous (damage-associated) molecular pattern factors (PAMPs and DAMPs, respectively). The development of novel TLR ligand-, pathway-, and/or target gene-specific therapeutics may have clinical utility in the management of the exuberant inflammatory/fibrotic tissue response to injury without compromising the host defense to pathogens. Recent Advances: DAMP ligands, released upon wounding, and microbial-derived PAMPs interact with several TLRs, and their various coreceptor partners, engaging downstream pathways that include Src family kinases, the epidermal growth factor receptor, integrins and the tumor suppressor phosphatase and tensin homolog (PTEN). Toll-like receptor 4 (TLR4) activation enhances cellular responses to the potent profibrotic cytokine transforming growth factor-β1 (TGF-β1) by attenuating the expression of receptors that inhibit TGF-β1 signaling. Critical Issues: Common as well as unique pathways may be activated by PAMP and DAMP ligands that bind to the repertoire of TLRs on various cell types. Dissecting mechanisms underlying ligand-dependent engagement of this complex, highly interactive, network will provide for adaptation of new and focused therapies directed to the regulation of pathologically significant profibrotic genes. Inherent in this diversity are therapeutic opportunities to modulate the pathophysiologic consequences of persistent TLR signaling. The recently identified involvement of receptor and nonreceptor kinase pathways in TLR signaling may present novel opportunities for pharmacologic intervention. Future Directions: Clarifying the identity and function of DAMP-activated TLR complexes or ligand-binding partners, as well as their engaged downstream effectors and target genes, are key factors in the eventual design of pathway-specific treatment modalities. Such approaches may be tailored to address the spectrum of TLR-initiated pathologies (including localized and persistent inflammation, maladaptive repair/fibrosis) and, perhaps, even titrated to achieve patient-unique beneficial clinical outcomes.