The role of NOD-like receptors in innate immunity

Abstract

The innate immune system in vertebrates and invertebrates relies on conserved receptors and ligands, and pathways that can rapidly initiate the host response against microbial infection and other sources of stress and danger. Research into the family of NOD-like receptors (NLRs) has blossomed over the past two decades, with much being learned about the ligands and conditions that stimulate the NLRs and the outcomes of NLR activation in cells and animals. The NLRs play key roles in diverse functions, ranging from transcription of MHC molecules to initiation of inflammation. Some NLRs are activated directly by their ligands, while other ligands may have indirect effects on the NLRs. New findings in coming years will undoubtedly shed more light on molecular details involved in NLR activation, as well as the physiological and immunological outcomes of NLR ligation.

Keywords: inflammasome; inflammation; innate immunity; nod-like receptors; pathogen recognition receptors; pathogen-associated molecular patterns; toll-like receptors.

Figure 1

Structure of the inflammasome complexes involving NOD-like receptors (NLRs). After ligand recognition, NLRP1, NLRP3 and NLRC4 bind to pro-caspase-1 via the adaptor ASC. The CARD domain of ASC is necessary to recruit pro-caspase-1. Nlrp1b and NLRC4 might also directly bind to pro-caspase-1 since these receptors contain the domain CARD. The assembly of the inflammasome complex leads to its oligomerization. Activation of the inflammasome complex (NLRP1, NLRP3 or NLRC4) ultimately leads to proteolytic activation of pro-caspase-1 into active caspase-1. Caspase-1 then cleaves gasdermin D (GSDMD) into a C-terminal portion and an N-terminal portion. The N-terminal portion inserts into the plasma membrane and oligomerizes to form pores that can lead to a type of cell death called pyroptosis, and contribute to the release of inflammasome-related cytokines. The active form of caspase-1 also cleaves pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18, respectively. The active form of these pro-inflammatory cytokines is then released from the cell.

Figure 2

Mechanisms and ligands involved in canonical and noncanonical inflammasome activation. (1) The NLRP3 inflammasome can be activated by a plethora of signals, including potassium efflux, mitochondrial ROS production, and extracellular ATP ligation to P2X7 receptor. (2) Muramyl dipeptide, SARS-CoV-2 infection, viral proteases and double-stranded viral RNA can lead to the activation of the human NLPR1 inflammasome. The lethal toxin produced by Bacillus anthracis activates murine Nlrp1b. (3) The noncanonical inflammasome is activated by intracellular LPS from Gram-negative bacteria. Intracellular LPS directly binds to caspase-11 (in mice) or caspase-4/-5 (in humans), which become activated. (4) The protein NAIP in humans can recognize T3SS (type III secretion system) needle protein, while the different rodent Naips can recognize different bacterial ligands, such as T3SS needle protein (Naip1), T3SS inner rod protein (Naip2), and flagellin (Naip5 and Naip 6). Following PAMP ligation, NAIPs bind to and activate the NLRC4 inflammasome.