McKeown-Longo Paula J, Higgins Paul J
Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, New York.
Adv Wound Care (New Rochelle). 2017 Oct 1;6(10):320-329. doi: 10.1089/wound.2017.0736.
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. 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. 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. 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.
慢性炎症和适应性不良修复会导致纤维化的发展，这会对生活质量和器官功能产生负面影响。Toll样受体（TLR）系统是组织对外源性（病原体相关）和内源性（损伤相关）分子模式因子（分别为PAMP和DAMP）作出反应的关键节点。开发新型TLR配体、信号通路和/或靶基因特异性疗法，可能在管理损伤后过度的炎症/纤维化组织反应方面具有临床应用价值，同时又不会损害宿主对病原体的防御能力。受伤时释放的DAMP配体和微生物来源的PAMP与多种TLR及其各种共受体相互作用，激活包括Src家族激酶、表皮生长因子受体、整合素以及肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）在内的下游信号通路。Toll样受体4（TLR4）的激活通过减弱抑制TGF-β1信号传导的受体表达，增强细胞对强效促纤维化细胞因子转化生长因子-β1（TGF-β1）的反应。结合到各种细胞类型上TLR库的PAMP和DAMP配体，可能会激活共同的以及独特的信号通路。剖析这种复杂、高度相互作用网络中配体依赖性参与的机制，将有助于开发针对调节具有病理意义的促纤维化基因的新型靶向疗法。这种多样性中蕴含着调节TLR持续信号传导病理生理后果的治疗机会。最近发现受体和非受体激酶信号通路参与TLR信号传导，这可能为药物干预提供新的机会。明确DAMP激活的TLR复合物或配体结合伙伴的身份和功能，以及它们所激活的下游效应器和靶基因，是最终设计通路特异性治疗模式的关键因素。此类方法可针对性地解决TLR引发的一系列病理问题（包括局部和持续性炎症、适应性不良修复/纤维化），甚至可能进行调整以实现针对患者个体的有益临床结果。
