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.
TLRs are extensively studied and evolutionarily conserved proteins that detect PAMPs. They were initially identified in Drosophila melanogaster as an essential gene because of its vital role in ontogenesis and immunological effects against fungal infections . To date, 10 TLR family members have been identified in humans (TLR1 to TLR10) . They are type I integral membrane glycoproteins characterized by their (1) extracellular domains containing varying numbers of leucine-rich repeat (LRR) motifs that are required for PAMP recognition and (2) a cytoplasmic signaling domain homologous to that of interleukin 1 receptor (IL-1R), termed the Toll/IL-1R homology (TIR) domain, which is essential for the activation of downstream signaling. The TIR domain interacts with multiple adaptor molecules and brings about the activation of nuclear factor (NF)-κB through the signal transmission that culminates in the synthesis of proinflammatory cytokines . Among TLRs, TLR1, TLR2, TLR4, TLR5, and TLR6 are mainly located on the surface of the cell and detect PAMPs from fungi, bacteria, and protozoa, whereas TLR3, TLR7, TLR8, and TLR9 are exclusively expressed within endocytic compartments and primarily recognize nucleic acids from various bacteria . Diverse TLRs exclusively detect specific DAMPs and PAMPs . TLR2 forms heterodimers with either TLR1 or TLR6, where TLR1 or TLR2 detects triacyl lipopeptides, while TLR2 or TLR6 specifically interacts with diacyl lipopeptides. TLR3 has high specificity for RNA ligands (double-stranded) that are products of viral replication at various stages. TLR4 recognizes LPS, i.e., the cell wall component of gram-negative bacteria; LPS requires an interaction with coreceptor MD2 to bind to TLR4. TLR5 identifies bacterial-flagellin–based ligands by its extracellular homodimeric domain. Both TLR7 and TLR8 respond to single-stranded RNA, whereas TLR9 interacts with CpG motif–containing ligands . TLRs switch on similar signaling components that are utilized for IL-1R signaling . Signaling through TLRs proceeds essentially through a well-described pathway in which various receptor-binding domains (TIR domains) transmit a signal through adapter molecules such as MyD88, TRIF (TICAM-1), TIRAP (MAL), and TRAM . These adaptor molecules stimulate specific transcription factors like IRF3/7, nuclear factor κB (NF-κB), and mitogen-activated protein kinases (MAPKs) to induce the expression of type I interferons and proinflammatory cytokines. All TLRs, except TLR3, engage MyD88, and launch MyD88-dependent signaling pathway to cause NF-κB and MAPKs to upregulate proinflammatory cytokines in dendritic cells and macrophages. On the other hand, TLR1, TLR2, TLR4, and TLR6 employ TIRAP to activate MyD88-dependent signaling. TLR3 and TLR4 initiate TRIF-dependent signaling to make NF-κB and IRF3 upregulate type I interferons and proinflammatory cytokines. TLR4 employs TRIF through a complementary adapter molecule, TRAM. Meanwhile, TLR4 triggers the TRIF-dependent signaling pathway together with MyD88 signaling by recruiting all four adapter molecules. First, TLR4 uses TIRAP, which enables MyD88 recruitment to induce MAPK and NF-κB activation. TLR4 is pushed to an endosome through dynamin-dependent endocytosis during TRIF-dependent signal transduction and forms a complex with TRIF and TRAM. This complex initiates TRIF-dependent signaling, which is essential for forcing IRF3 to upregulate a type 1 interferon and the second phase of NF-κB and MAPK stimulation to trigger the production of inflammatory cytokines . In dendritic cells, a protein limited to the endoplasmic reticulum, UNC93B1, plays an integral part in the transport of endosome-localized TLRs, including TLR3, TLR7, and TLR9. Mice that carry a mutation in this protein show absolute absence of all cytokine production after encountering respective PAMPs .
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 . 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 . 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 . NLRs play a vital part in the protection of the body from various infectious diseases caused by viruses, bacteria , helminths , fungi, and protists . 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 . Alternatively, some NLRs have an essential role in development and inflammation . 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 . 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 . NLRC2 identifies another peptidoglycan fragment called muramyl dipeptide . Then, NLRC1 and NLRC2 proceed with the help of adaptor molecule RIPK2 to start up MAPK and NF kB signaling pathways .
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 . 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 . 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) . 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 .
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 . 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 . Post-translational modifications have been proved to be crucially engaged in the activation of NLRP3 . Nevertheless, deubiquitination and dephosphorylation can also result in its activation .
Moreover, phosphorylation of protein kinase A–related NLRP3 on the Ser21 residue is critical for triggering the NLRP3 inflammasome . Recent studies revealed the function of microRNAs, e.g., myeloid-derived miR-223, in activating the NLRP3 inflammasome, such as myeloid-derived miR 223 . 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 
This knowledge has further improved understanding of the phenomena caused by epigenetic regulators during inflammasome stimulation .