NLRP6: A Multifaceted Innate Immune Sensor

NLRP6 is highly expressed in the small and large intestine, and has both inflammasome-dependent and -independent roles in the maintenance of intestinal homeostasis. NLRP6 inflammasome-induced interleukin (IL)-18 is modulated by microbial metabolites, and downstream IL-18 secretion induces an antimicrobial peptide program in intestinal epithelial cells that is critical to prevent dysbiosis. NLRP6 in sentinel goblet cells is required for mucus production, thereby preventing the invasion of enteric bacteria into the mucosal layer in an inflammasome-dependent, but IL-18-independent manner. In association with the helicase DHX15, NLRP6 is involved in antiviral responses upon viral RNA sensing, in an inflammasome-independent manner. In myeloid cells, NLRP6 negatively regulates NF-κB signaling and thereby suppresses inflammatory responses. NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, regulates inflammation and host defense against microorganisms. Similar to other NLRs, NLRP6 not only participates in inflammasome formation, but is also involved in nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling regulation and facilitation of gastrointestinal antiviral effector functions. Additionally, NLRP6 contributes to the regulation of mucus secretion and antimicrobial peptide production, thereby impacting intestinal microbial colonization and associated microbiome-related infectious, autoinflammatory, metabolic, and neoplastic diseases. However, several of the mechanisms attributed to the functions of NLRP6 remain debatable, leaving open questions as to the relevant molecular mechanisms and interacting partners, and putative human relevance. We herein discuss recent findings related to NLRP6 activity, while highlighting outstanding questions and future perspectives in elucidating its roles in health and disease. NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, regulates inflammation and host defense against microorganisms. Similar to other NLRs, NLRP6 not only participates in inflammasome formation, but is also involved in nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling regulation and facilitation of gastrointestinal antiviral effector functions. Additionally, NLRP6 contributes to the regulation of mucus secretion and antimicrobial peptide production, thereby impacting intestinal microbial colonization and associated microbiome-related infectious, autoinflammatory, metabolic, and neoplastic diseases. However, several of the mechanisms attributed to the functions of NLRP6 remain debatable, leaving open questions as to the relevant molecular mechanisms and interacting partners, and putative human relevance. We herein discuss recent findings related to NLRP6 activity, while highlighting outstanding questions and future perspectives in elucidating its roles in health and disease. an abnormal microbiome community, impacting the taxonomic composition as well as the metagenomic and metabolic function of the microbial community, that is linked to disease development. Compared with the healthy state, dysbiosis typically features blooms of pathobionts, and loss of commensals and diversity. Once the microbiota configuration is shifted, dysbiosis persists as a stable state and can assume various compositional manifestations, depending on the trigger. Several factors can drive the development of dysbiosis, including infection by a pathogen, diet, and xenobiotics, familial transmission, as well as genetics. a protein complex that functions as a sensor of the innate immune system, recognizing a diverse set of stimuli. Inflammasomes regulate the activation of caspase-1 and the production of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. PRRs are important components of the inflammasome complex, among them NLRs and ALRs. Upon activation, the inflammasome complex oligomerizes to activate caspase-1, with or without the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). A non-canonical inflammasome formed by caspase-11 can activate caspase-1, detect intracellular lipopolysaccharide (LPS) and intracellular bacteria, and mediate pyroptotic cell death and IL-1α secretion, but not IL-1β secretion. the mammalian host harbors a dense microbial community, termed the ‘microbiota’. This complex community of microorganisms colonizes the gastrointestinal tract, respiratory system, skin, and urogenital system. The microbiota comprises bacteria, viruses, and eukaryotic microbes. cells of the innate immune system utilize germ line-encoded PRRs to sense the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Several classes of PRR exist and can be classified according to their ligand, the downstream signaling pathway as well as the type of immune response modulation. PRRs include Toll-like receptors (TLRs), C-type lectins (CTLs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), AIM2-like receptors (ALRs), and OAS-like receptors (OLRs).