Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis

Abstract

Inflammasomes are involved in gut homeostasis and inflammatory pathologies, but the role of NLRP3 inflammasome in these processes is not well understood. Cryopyrin-associated periodic syndrome (CAPS) patients with NLRP3 mutations have autoinflammation in skin, joints, and eyes, but not in the intestine. Here we show that the intestines of CAPS model mice carrying an Nlrp3 R258W mutation maintain homeostasis in the gut. Additionally, such mice are strongly resistant to experimental colitis and colorectal cancer; this is mainly through a remodelled gut microbiota with enhanced anti-inflammatory capacity due to increased induction of regulatory T cells (Tregs). Mechanistically, NLRP3R258W functions exclusively in the lamina propria mononuclear phagocytes to directly enhance IL-1β but not IL-18 secretion. Increased IL-1β boosts local antimicrobial peptides to facilitate microbiota remodelling. Our data show that NLRP3R258W-induced remodelling of the gut microbiota, induces local Tregs to maintain homeostasis and compensate for otherwise-detrimental intestinal inflammation.

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…Another possible explanation is based on the presence or absence of an environmental factor, such as a microbiome-related development of suppressor cells, that prevents the development of GI disease. This possibility is supported by the recent finding already mentioned above (26), showing that, in mice, a CAPS-like mutation in NLRP3 leading to increased NLRP3 inflammasome activity results in the appearance of a gut organism capable of inducing the development of suppressor T cells. Further work will be necessary to establish these or other explanations of intestinal inflammation in the face of NLRP3 overactivity.…”

“…Thus, in a study by Yao et al, it was shown that mice bearing a mutation in the NLRP3 gene resulting in NLRP3 with increased function similar to that occurring in the autoinflammatory Muckle-Wells syndrome were resistant to DSS-colitis. This was due to IL-1β induction of antibacterial peptides promoting the development of an intestinal microflora containing an organism (Larus marinus) that induces regulatory T cells in the mucosa capable of suppressing inflammation (26).…”

The inflammasomes, immune guardians at defence barriers

“…However, these studies fail to show a specific role for epithelial cells, despite these being the main cell type affected by IBD. In fact, recent studies suggest that NLRP3 is not expressed by epithelial cells in the colon of mice, placing tissue‐resident macrophages as the principal contributors to this NLRP3‐dependent response . These studies suggest that although NLRP3 is a main actor in IBD, the epithelial cell layer's contribution to IBD might be NLRP3 independent.…”

“…In fact, recent studies suggest that NLRP3 is not expressed by epithelial cells in the colon of mice, placing tissue-resident macrophages as the principal contributors to this NLRP3-dependent response. 71 These studies suggest that although NLRP3 is a main actor in IBD, the epithelial cell layer's contribution to IBD might be NLRP3 independent. Surprisingly, epithelial cell-specific depletion of capase-1 induces decreased IL-18 levels and decreased pathology in a DSS-induced colitis model, pointing to the involvement of another inflammasome-forming receptor.…”

The emerging roles of inflammasome‐dependent cytokines in cancer development

“…Consistent with its role in promoting antitumorigenic interferon-c production, Th1 cell, NK and cytotoxic Tcell (CD8 + T cells) responses [105,115,116], mice lacking IL-18 or its cognate receptor were reported to be hypersusceptible to colitisassociated tumorigenesis in the murine azoxymethane (AOM)/ dextran sodium sulphate (DSS) model of inflammation-associated colorectal cancer [117]. Consistently, other studies showed that AOM/DSS-treated NLRP3 À/À , Nlrp3 R258W , ASC À/À and caspase-1 À/À mice had an increased tumour burden [118][119][120]. Conversely, another study [121] failed to observe changes in colorectal cancer development in AOM/DSS-treated NLRP3 À/À mice, arguing against a tumour-suppressive role for IL-18.…”