NLRP3 Inflammasome in Inflammatory Bowel Disease: Friend or Foe?

Excerpt

Inflammasomes are large multimeric protein complexes (Fig. 1) that actively regulate cellular immunity and homeostasis through sensing and responding to either intracellular or extracellular stimuli [1, 2]. They are grouped on the basis of their sensor proteins, including nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing receptors (NLRs), absent in melanoma-2 receptor (AIM2), and pyrin (Fig. 1a). The NLR family of intracellular innate immune receptors has more than 20 known members, including NLRP1, NLRP3, NLRP6, NLRP12, and NLRC4. The NLR family has two subfamilies, NLRP and NLRC, based on their N-terminal domains: NLRP contains a pyrin domain (PYD), whereas NLRC contains a caspase activation and recruitment domain (CARD) domain (Fig. 1a, b). Homotypic interactions between the pyrin domain of NLRP3 and the adaptor molecule apoptosis-associated spec-like protein containing CARD (ASC) bridge the association of caspase-1 to NLRP3 in a large protein complex termed the NLRP3 inflammasome (Fig. 1b). The NLRP3 inflammasome is one of the most studied subfamily members of inflammasomes, sensing and activated by a sizeable spectrum of pathogen-associated patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Little is known about the negative regulator of the NLRP3 inflammasome, except that a recent report has suggested interleukin (IL)-10 functions as a potent suppressor in cultured macrophages and in mice [3]. Activated caspase-1 converts the cytosolic precursors of proinflammatory cytokine IL-1β or IL-18 into biologically active forms (Fig. 1c), which substantially contribute to the pathogenesis of several autoinflammatory diseases, including Muckle–Wells syndrome, familial cold autoinflammatory syndrome, chronic infantile neurological cutaneous and articular (CINCA) syndrome, gouty arthritis, Alzheimer’s disease, silicosis, and alcoholic liver disease.

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