The breach of the host immune system by pathogenic microorganisms generates an array of immune reactions through the synergy between the diversified cluster of pathogen-based virulence factors and defensive immune processes of the host. The host–pathogen encounter usually launches immune reactions via identification of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs). Active recognition of a PAMP immediately elicits an immune response in the host by stimulating multiplex signaling pathways that climax in the inflammatory responses regulated by numerous chemokines and cytokines, which consequently promote the elimination of the harmful microorganism carrying the PAMP, such as viral double-stranded ribonucleic acid (RNA) and lipopolysaccharides (LPS). Moreover, the innate immune system expands efficient defense against pathogenic microbes by initiating adaptive immunity, which involves immunological memory and is long-lasting. Adaptive immunity is characterized by the formation of antigen-specific T and B lymphocytes via gene rearrangement.
This group of molecules recognizes a broad range of ligands inside the cell cytoplasm. In the last few years, the vital role of the NLRP family was widely recognized [22][23]. This class of molecules consists of approximately 34 members in mice and 23 members in humans. NLRs respond to metabolic stress and microbial byproducts by causing inflammation with the inflammasome assembly: a huge cytoplasmic complex that stimulates various inflammatory caspases that bring about the synthesis of IL-1β and IL-18 [24]. NLRs are large multidomain tripartition proteins and usually possess an inner nucleotide-binding region designated as the NACHT domain (also frequently referred to as the NOD domain). A C-terminal domain incorporates a receptor domain that carries repeating LRRs, and N-terminal domains serve for attachment to downstream pathway molecules. It is believed that the oligomerization of the NACHT domain is critical for the triggering of NLRs; therefore, establishing an effective signaling platform, e.g., a NODosome or inflammasome, is necessary to attach to the effector protein subunits and adapter molecules in order to elicit an inflammatory response [25][26]. NLRs play a vital part in the protection of the body from various infectious diseases caused by viruses, bacteria [27], helminths [28], fungi, and protists [29][30]. The NLRs studied so far are categorized into four classes: (1) MAPK and NF kB activators, (2) activators of the inflammasome, (3) trans-activators of MHC expression, and (4) inflammatory-signal inhibitors. Meanwhile, various NLRs perform a certain function in several biological mechanisms, such as fetal development and embryogenesis [31]. Alternatively, some NLRs have an essential role in development and inflammation [32]. On the other hand, a few NLRs, such as NLRP3, recognize DAMPs, e.g., side products of sterile cellular damage (like uric acid or pathogen invasions, such as extracellular ATP release or reactive oxygen species [33][34]. One group of NLRs that modulates MAPKs and NF kB includes NLRC1 and NLRC2. NLRC1 identifies iE-DAP, a peptidoglycan component and a building block of the bacterial walls [35]. NLRC2 identifies another peptidoglycan fragment called muramyl dipeptide [36][37]. Then, NLRC1 and NLRC2 proceed with the help of adaptor molecule RIPK2 to start up MAPK and NF kB signaling pathways [38].
Inflammasomes have an inherent capability to induce an innate immune response after recognition of a DAMP or PAMP. The molecular patterns are identified through PRRs or endosomal compartments (e.g., TLRs) or in the cytoplasm, i.e., RIG-I–like receptors (RLRs). Engagement of these PRRs stimulates downstream signaling pathways that drive a release of proinflammatory cytokines [39][40]. Among these cytokines, few are synthesized in their precursor state, which is mandatory to be converted into a functionally active mature form. Various cellular components (such as the inflammasome) are crucial for this activation, ultimately resulting in the secretion of cytokines in their active state (as inflammatory markers) from some cells. The innate immune system triggers the inflammasome's triggering through a mechanism recently analyzed in numerous studies [41][42][43]. In both mice and humans, the leading players of the inflammasome are PRRs such as NLRs and "not present in melanoma 2–like receptors" (AIM2-like receptors) [44]. Various inflammasomes have been investigated, including the NLR family pyrin domain–containing 3 (NLRP3), AIM2, NLRP1, and NLRC4 types. NLRP3 is a member of the NLRP subfamily and contains a pyrin domain (PYD) at its N terminus. NLRP3 has been widely studied due to its integral role in immunity and immune-system–related diseases. In addition, NLRP3 is involved in the pathogenesis of numerous neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and metabolic diseases, e.g., atherosclerosis, obesity, and type 2 diabetes mellitus [45][46].
Various factors have been documented that activate the NLRP3 inflammasome, although the exact mechanism is still unknown and needs further research. A possible mechanism behind the triggering of the NLRP3 inflammasome involves the production of reactive oxygen species, impairment of mitochondrial function, discharge of mitochondrial DNA, K+ efflux, a release of cathepsin B from damaged lysosomes, an imbalance of extracellular Ca2+ concentration, and the emergence of transmembrane holes [12][13][14]. Furthermore, NIMA-related kinase 7 (NEK7) is believed to attach to the LRR domain of NLRP3 and hence to carry out its activation by oligomerization [15]. Post-translational modifications have been proved to be crucially engaged in the activation of NLRP3 [16]. Nevertheless, deubiquitination and dephosphorylation can also result in its activation [17][18].
Moreover, phosphorylation of protein kinase A–related NLRP3 on the Ser21 residue is critical for triggering the NLRP3 inflammasome [19]. Recent studies revealed the function of microRNAs, e.g., myeloid-derived miR-223, in activating the NLRP3 inflammasome, such as myeloid-derived miR 223 [20]. Additionally, miR-33 has been reported to perform an essential function in the pathogenesis of rheumatoid arthritis through the modulation of the NLRP3 inflammasome in macrophages [21]
This knowledge has further improved understanding of the phenomena caused by epigenetic regulators during inflammasome stimulation [46].
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics12100955