Regulation of TLR by endogenous ligand

Diverse molecules of host-cell origin may serve as endogenous ligands of Toll-like receptors (TLRs) (Erridge C 2010; Piccinini AM & Midwood KS 2010). These molecules are known as damage-associated molecular patterns (DAMPs). DAMPs are immunologically silent in healthy tissues but become active upon tissue damage during both infectious and sterile insult. DAMPs are released from necrotic cells or secreted from activated cells in response to tissue damage to mediate tissue repair by promoting inflammatory responses. However, DAMPs have also been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA), cancer, and atherosclerosis. The mechanism underlying the switch from DAMPs that initiate controlled tissue repair, to those that mediate chronic, uncontrolled inflammation is still unclear. Recent evidence suggests that an abnormal increase in protein citrullination is involved in disease pathophysiology (Anzilotti C et al. 2010; Sanchez-Pernaute O et al. 2013; Sokolove J et al. 2011; Sharma P et al. 2012). Citrullination is a post-translational modification event mediated by peptidyl-arginine deaminase enzymes which catalyze the deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions.

多种源自宿主细胞的分子可能充当Toll样受体（TLRs）的内源性配体（Erridge C 2010；Piccinini AM & Midwood KS 2010）。这些分子被称为损伤相关分子模式（DAMPs）。在健康组织中，DAMPs在免疫学上处于沉默状态，但在感染性和无菌性损伤导致的组织损伤过程中，它们会变得活跃。DAMPs可以从坏死细胞中释放，或由激活的细胞分泌，以响应组织损伤，通过促进炎症反应来介导组织修复。然而，DAMPs也被认为与许多炎症性和自身免疫性疾病的发生机制有关，包括类风湿性关节炎（RA）、癌症和动脉粥样硬化。从启动受控组织修复的DAMPs到介导慢性、不受控制的炎症的DAMPs之间的转换机制尚不明确。近期的研究证据表明，蛋白质去酰胺化异常增加与疾病病理生理学有关（Anzilotti C 等人 2010；Sanchez-Pernaute O 等人 2013；Sokolove J 等人 2011；Sharma P 等人 2012）。去酰胺化是一种由肽基精氨酸脱氨酶酶介导的翻译后修饰事件，这些酶通过在钙离子的存在下将精氨酸残基转化为瓜氨酸来催化蛋白质的去酰胺化。