Nlrp6

NLRPs (acronym for "NIGHT, LRR and PYD domains-containing protein) are, together with the NOD1 and NOD2 proteins, members of the NLR (Nod-like Receptor) protein family and play a major role in innate immunity as pathogen recognition receptors (PPRs). Like the NOD proteins, NLRPs are expressed exclusively cytoplasmically. All NLRPs (they all contain a pyrin domain) are encoded by a common gene family in humans. NLRPs are characterised by their ability to activate different inflammatory complexes.

Inflammasomes are differently composed cytosolic protein complexes, whereby the different NLRPs are of great importance for their functionality. Inflammasomes are predominantly found in immune cells such as dendritic cells and macrophages.

The activation of an inflammasome complex leads to the expression of different caspases, which convert inactive interleukin-1beta and interleukin-18 into their active form.

NLRP6, NIGHT, LRR and PYD domains-containing protein 6 also known as NALP6 is a cytosolic protein encoded in humans by the NLRP6 gene located on chromosome 11: 0.28 - 0.29.

The functions of the NLRP6 protein could only recently be characterized more precisely. NLRP6 is involved in the formation of inflammasomes. NLRP6 inhibits NF-κB and MAP kinases and suppresses antimicrobial defence (Anand PK et al.2013). Thus, NLRP6 proteins play an important role in the functionality of inflammatory monocytes (influencing IL-18-dependent TNF-alpha production).

Furthermore, NLRP6 is involved in the regulation of intestinal mucus production; NLRP6 reduces the production of antimicrobial peptides (Levy M et al. 2017) and is thus involved in the functionality of the intestinal barrier against pathogens (Seregin SS et al.2017).

NLRP6 and NLRP12 play an essential role in the balance of intestinal homeostasis and are negative regulators of inflammatory bowel reactions. NLRP6 regulates intestinal inflammation by balancing the composition of the intestinal microbiota (Anand PK et al. 2012; Chen GY 2014).

It has been shown that microbiota-associated metabolites such as taurine, histamine, and spermine can alter the microbiome by modulating the NLRP6-induced inflammation regulation (especially the epithelial IL-18 secretion and the antimicrobial peptides are influenced (Levy M et al.2015).

Artificially produced enteritides suppress the expression of NLRP6 but not of NLRP3 in animal experiments. Possibly, this suppression is caused by an enteritis-induced, increased release of the corticotropin-releasing hormone (Sun Y et al. 2013).

Animal experiments have also shown that NLRP6 plays an important role in the defence against enteric viruses. NlRP6 is able to bind viral RNA via the RNA helicase Dhx15. After detection of the viral pathogen, type I/III interferons are expressed and IFN-stimulable genes (ISGs) are activated (Wang P et al. 2015).

1. Anand PK et al (2012) Targeting NLRP6 to enhance immunity against bacterial infections. Future Microbiol 7:1239-1242.
2. Anand PK et al. (2012) NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488: 389-393.
3. Anand PK et al.(2013) NLRP6 in infection and inflammation. Microbes Infect 15:661-668.
4. Chen GY (2014) Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis. Eur J Immunol 44:321-327.
5. Chen GY et al (2011) A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J Immunol 186:7187-7194.
6. Elinav E et al (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745-757.
7. Levy M et al(2015) Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling. Cell 163:1428-1443.
8. Levy M et al (2017) NLRP6: A Multifaceted Innate Immune Sensor. Trends Immunol 38:248-260.
9. Seregin SS et al (2017) NLRP6 function in inflammatory monocytes reduces susceptibility to chemically induced intestinal injury. Mucosal Immunol 10:434-445.
10. Sun Y et al (2013) Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology 144:1478-1487.
11. Wang P et al (2015) Nlrp6 regulates intestinal antiviral innate immunity. Science 350:826-30.