INTRODUCTION
The innate immune system is the first line of host defense that induces immediate, non-specific immune responses against pathogens (1). Inflammation is part of the innate immune system and is initiated when the innate immune system recognizes invading pathogens or molecules from tissue injury through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and inflammasomes of the innate immune system (2,3).
Although inflammation is a protective response to eliminate harmful stimuli, initiate tissue repair, and restore health, it can also contribute to the development of various diseases, such as autoimmune diseases, cardiovascular diseases, and neurodegenerative diseases, if it is not properly regulated or resolved (4,5).
Damage-associated molecular patterns (DAMPs) are molecules released upon cellular stress or tissue injury and are regarded as endogenous danger signals, because they induce potent inflammatory responses by activating the innate immune system during non-infectious inflammation (6,7). Recently, emerging evidence has indicated that DAMPs play a key role in the pathogenesis of human diseases by inducing inflammation (8). This review describes the role of DAMPs in inflammatory diseases and the possibility of using DAMPs as biomarkers and therapeutic targets for these inflammatory diseases.
ORIGIN AND LIST OF DAMPS
Since the danger model was introduced by Polly Matzinger (9), several DAMPs have been identified, and the number of DAMPs is still increasing (7,10).
DAMPs are released from the extracellular or intracellular space following tissue injury or cell death (10). These DAMPs are recognized by macrophages, and inflammatory responses are triggered by different pathways, including TLRs and inflammasomes (10,11).
DAMPs can originate from different sources and include extracellular proteins, such as biglycan and tenascin C, and intracellular proteins, such as high-mobility group box 1 (HMGB1), histones, S100 proteins, heat-shock proteins (HSPs), and plasma proteins, like fibrinogen, Gc-globulin, and serum amyloid A (SAA) (10,12-15). A list of well-characterized DAMPs, along with their origin and receptors, is shown in Table 1.
HMGB1, a member of the HMG protein family, which is located in the cell nucleus, has a critical function in gene expression, but when released to the extracellular space, HMGB1 is known to induce inflammation by activating the NF-κB pathway by binding to TLR2, TLR4, TLR9, and the receptor for advanced glycation end products (RAGE) (16). S100 proteins are calcium-binding proteins, and their main function is the management of calcium storage and shuffling (10,17). Although S100 proteins have various functions, which include cell proliferation, differentiation, migration, and energy metabolism under healthy conditions (17), they also act as DAMPs by interacting with TLR2, TLR4, and RAGE after they are released from phagocytes (18).
Likewise, HSPs normally function as chaperones and assist with biosynthetic pathways (10), but extracellular HSPs, which are cellular necrosis products, can induce inflammation through the activation of TLR2, TLR4, and CD91 (10,19). Adenosine triphosphate (ATP) and uric acid, which are purine metabolites, also activate NLR family, pyrin domain containing (NLRP) 3 inflammasomes to induce IL-1β and IL-18 (20,21). Finally, some plasma proteins, including SAA, fibrinogen, Gc-globulin, α1-microglobulin, and α2-macroglobulin, are extravasated to the sites of inflammation from the vasculature and function as DAMPs by stimulating macrophages to produce inflammatory cytokines through TLR2 or TLR4 (12-15).
PRRS
PRRs are important components of the innate immune system. Several families of PRRs have been identified in the diverse compartments of the cell (Table 2).
They recognize microbes or tissue damage by specific molecular structures called pathogen-associated molecular patterns (PAMPs) or DAMPs (10,22). The main functions of PRRs are to stimulate phagocytosis and mediate inflammation by sensing various pathogens and molecules from damaged cells (2,23). As a result, PRRs activate inflammatory signaling pathways to induce innate immunity (23).
TLRs are type I transmembrane glycoproteins located at the cell surface (TLR1, 2, 4, 5, 6, and 10) or in intracellular membranes (TLR3, 7, 8, and 9) and recognize various PAMPs or DAMPs (24). TLRs induce the production of proinflammatory cytokines and type I interferons (IFNs) through the myeloid differentiation factor 88 (MyD88)-dependent signaling pathway or the toll/interferon response factor (TRIF)-dependent signaling pathway (24). NOD-like receptors (NLRs) are cytoplasmic PRRs that include NODs, NLRPs, and the IPAF subfamily (25,26).
NOD1 and NOD2 initiate proinflammatory signaling by activating NF-κB (25), and NLRP3 stimulation by DAMPs, such as extracellular ATP, hyaluronan, and uric acid, can activate caspase-1 and induce the release of IL-1β and IL-18 through the formation of an inflammasome (26). RIG-like receptors (RLRs), including RIG-I, MDA5, and LGP2, detect viral RNA and self RNA in the cytoplasm (27). RLRs induce the production of IFNs by interacting with IPS-1; furthermore, RLR signaling cross-talks with the TLR or the inflammasome signaling pathway (27).
C-type lectin receptors (CLRs), expressed by dendritic cells (DCs), promote NF-κB activation by modulating TLR signaling or directly through the spleen tyrosine kinase (SYK) and RAF1 pathways (28). Scavenger receptors consist of a large family of proteins and recognize various patterns. RAGE, one of the scavenger receptors, interacts with PAMPs or DAMPs, such as advanced glycation end products (AGEs), HMGB1, and S100 proteins, thereby mediating inflammation, oxidative stress, and apoptosis (29).