Defective regulation of TLR7 by endogenous ligand

Activation of innate immune receptors including Toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) is crucial in the host defense against microbial infections. On the other hand, these receptors are also activated by diverse molecules of host-cell origin. These molecules are known as damage-associated molecular patterns (DAMPs). This Reactome module describes defects in activation of TLRs by the endogenous ligands. <p>DAMPs are released from necrotic cells or secreted from activated cells in response to tissue damage to mediate tissue repair by promoting inflammatory responses (reviewed by Piccinini AM et al., 2010; Gong T et al., 2020; Zindel LJ et al., 2020). However, DAMPs have also been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and atherosclerosis (Duffy L & O’Reilly SC 2016; Fukuda D et al., 2019; Gong T et al., 2020; Liu J et al., 2022). There is a correlation between high level of endogenous TLR ligands and different chronic inflammatory conditions in human subjects and mouse models (Duvvuri B & Lood C et al., 2019; Negishi H et al., 2019; Punnanitinont A et al., 2022). The mechanism underlying the switch from DAMPs that initiate controlled tissue repair, to those that mediate chronic, uncontrolled inflammation is still unclear. Studies suggest 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; Olsen I et al., 2018). Moreover, gene polymorphisms within TLRs may predispose to the abnormal inflammatory responses associated with chronic diseases including autoimmune diseases (Devarapu SK & Anders HJ 2018; Zhang Y et al., 2021). For example, polymorphisms that increase expression of TLR7 are associated with a higher risk of SLE (reviewed in Fillatreau S et al., 2021). Further, inherited genetic variations can promote autoimmune responses. For example, TLR7 Y264H was identified as a gain-of-function mutation in a patient with SLE (Brown GJ et al., 2022). TLR7 Y264H exhibited enhanced affinity to endogenous guanosine-containing ligands (Brown GJ et al., 2022).

天然免疫受体，尤其是Toll样受体（TLRs）的激活，由病原体相关分子模式（PAMPs）触发，对宿主抵御微生物感染至关重要。另一方面，这些受体亦受宿主细胞来源的多种分子的激活。此类分子被称为损伤相关分子模式（DAMPs）。本Reactome模块描述了TLRs激活的内源性配体缺陷。DAMPs在组织损伤的应激下，由坏死细胞释放或由激活细胞分泌，以促进炎症反应介导的组织修复（参见Piccinini AM等，2010年；Gong T等，2020年；Zindel LJ等，2020年的综述）。然而，DAMPs亦被牵涉到许多炎症性和自身免疫性疾病的发生机制，包括类风湿性关节炎（RA）、系统性红斑狼疮（SLE）和动脉粥样硬化（Duffy L & O’Reilly SC 2016；Fukuda D等，2019；Gong T等，2020；Liu J等，2022）。在人类受试者和小鼠模型中，高水平的内源性TLR配体与不同的慢性炎症状况存在关联（Duvvuri B & Lood C等，2019；Negishi H等，2019；Punnanitinont A等，2022）。DAMPs从启动可控性组织修复的DAMPs转换至介导慢性、失控性炎症的DAMPs之间的转换机制尚不明确。研究表明，异常增高的蛋白质瓜氨酸化在疾病病理生理学中扮演着重要角色（Anzilotti C等，2010；Sanchez-Pernaute O等，2013；Sokolove J等，2011；Sharma P等，2012；Olsen I等，2018）。此外，TLRs内部的基因多态性可能增加了与慢性疾病，包括自身免疫性疾病相关的异常炎症反应的易感性（Devarapu SK & Anders HJ 2018；Zhang Y等，2021）。例如，增加TLR7表达的多态性与SLE的更高风险相关（参见Fillatreau S等，2021年的综述）。进一步而言，遗传变异的遗传可以促进自身免疫反应。例如，TLR7 Y264H被识别为一名SLE患者中的功能获得性突变（Brown GJ等，2022）。TLR7 Y264H对内源性鸟苷酸类配体展现出增强的亲和力（Brown GJ等，2022）。