Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis

Abstract

There has been significant interest in understanding how interactions between the host immune system and the gut microbiota regulate intestinal homeostasis. Recent data suggest that the Nod-like receptor (NLR) family of PRRs regulate both the composition of the gut microbiota and innate immune signaling pathways that prevent pathologic intestinal inflammation and tumorigenesis. In this review, we will focus on NLRP6 and NLRP12, two members of the NLR family that have emerged as important players in the maintenance of intestinal homeostasis, and discuss the signaling pathways engaged by these receptors as well as the current models of how these receptors protect against the development of colitis and tumorigenesis.

Keywords: Cancer; Immune regulation; Immune responses; Inflammation; Innate immunity.

Figure 1. Multiple mechanisms involved in suppressing inflammation and tumorigenesis by NLRP6 and NLRP12

NLRP6 regulates IL-18 production, which helps maintain a healthy microbiome and promotes epithelial repair (1). IL-18 also downregulates IL-22BP (2), thereby allowing IL-22 to participate in epithelial proliferation and repair of epithelial damage. NLRP6-deficiency is also associated with persistent IL-22BP production by primarily MCHII⁺CD11c⁺ cells [35], which results in inhibition of the reparative activity of IL-22 (2). IL-18 potentially upregulates IFN-γ production, which promotes anti-tumor responses (3). In the absence of Nlrp6, the microbiome is altered, leading to the accumulation of potentially colitogenic bacteria, or dysbiosis (4), which can upregulate inflammatory factors, including CCL5 to promote inflammation and tumorigenesis especially in the presence of a damaged epithelial barrier (5). The persistence of epithelial damage allows bacterial translocation into the colonic mucosa to stimulate an aberrant inflammatory response by immune cells that promote inflammation and tumorigenesis (5). Similarly, NLRP12 negatively regulates NF-κB responses (6) although there are discordant observations regarding canonical versus non-canonical NF-kB pathways. NLRP12 deficiency is also associated with increased inflammation followed by tumorigenesis related to uncontrolled NF-κB signaling in either hematopoietic and/or nonhematopoietic cells (6).