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Review

Advances in Understanding Activation and Function of the NLRC4 Inflammasome

Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Thomas A. Kufer
Int. J. Mol. Sci. 2021, 22(3), 1048; https://doi.org/10.3390/ijms22031048
Received: 31 December 2020 / Revised: 14 January 2021 / Accepted: 16 January 2021 / Published: 21 January 2021
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1–mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro–IL-1β and pro–IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Salmonella Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease. View Full-Text
Keywords: NOD-like receptors; NLR; NLRC4; NAIP; IRF8; inflammasome; cell death; pyroptosis; apoptosis; necroptosis; PANoptosis; PANoptosome; Gram-negative bacteria; Salmonella NOD-like receptors; NLR; NLRC4; NAIP; IRF8; inflammasome; cell death; pyroptosis; apoptosis; necroptosis; PANoptosis; PANoptosome; Gram-negative bacteria; Salmonella
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MDPI and ACS Style

Sundaram, B.; Kanneganti, T.-D. Advances in Understanding Activation and Function of the NLRC4 Inflammasome. Int. J. Mol. Sci. 2021, 22, 1048. https://doi.org/10.3390/ijms22031048

AMA Style

Sundaram B, Kanneganti T-D. Advances in Understanding Activation and Function of the NLRC4 Inflammasome. International Journal of Molecular Sciences. 2021; 22(3):1048. https://doi.org/10.3390/ijms22031048

Chicago/Turabian Style

Sundaram, Balamurugan, and Thirumala-Devi Kanneganti. 2021. "Advances in Understanding Activation and Function of the NLRC4 Inflammasome" International Journal of Molecular Sciences 22, no. 3: 1048. https://doi.org/10.3390/ijms22031048

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