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.
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).
