NLRP12-Protein

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.

NLRP12 is a cytosolic protein encoded in humans by the NLRP12 gene located on chromosome 19q13.42 within a cluster of other NLRP genes.

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.

Most short NLRPs have an N-terminal pyrin domain (PYD), followed by the NIGHT domain, a NIGHT-associated domain (NAD), and a C-terminal leucine-rich region (LRR). NLRP12 has a regulatory function in the innate and adaptive immune system.

There is a body of evidence that a subset of NLR proteins, particularly the NLRP12 receptor protein
inhibittranscription of
the factor NF-κB. Dysregulated NF-κB activity is associated with inflammatory colonic diseases.
NLRP12-deficient mice develop colitis-associated colon cancer in addition to colitis (Allen IC et al. 2012). Furthermore, they respond to antigen immunization with a hyperinflammatoryT cell response.

Missens mutations in the NLRP12 gene are found in populations with periodic fever syndrome (Vitale A et al.2013; Lukens JR et al. 2015).

Borte S et al. reported in 2014 a 20-year-old patient with common variable immunodeficiency (CVID) who was found to have a mutation in the NLRP12 gene. This patient developed abdominal amyloidosis. Although systemic amyloidosis is not a rarity in CVID, a pathogenetic link has been postulated.

A new class of autoinflammatory syndromes are termed NLRP12-associated disorders (NLRP12AD). Etiopathologically, mutations in the NLRP12 gene underlie this particular group of diseases. Excessive increase of
IL-1β secretion (80-175 fold) cause the inflammatory disease symptoms. In these patients, dramatic improvement can be achieved with anakinra .

A Caucasian family was found to have a missense mutation (p.D294E) in the NLRP12 gene in familial cold urticaria.
NLRP12-mutated monocytes showed neither an increase in NF-κB activity nor increased IL-1β secretion. However, the kinetics of PAMP-induced IL-1β secretion was significantly accelerated. Furthermore, there was an increased production of reactive oxygen species (ROS).(Borghini S et al. 2011).

1. Allen IC et al (2012) NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. Immunity 36:742-754 .
2. Borte S et al (2014) Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency. Clin Immunol 154:105-111.
3. Jéru I et al (2011) Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum 63:1459-1464.
4. Jéru I et al (2011) Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis Rheum 63:2142-2148.
5. Lukens JR et al (2015) The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells. Immunity 42:654-664.
6. Vitale A et al.(2013) Rare NLRP12 variants associated with the NLRP12-autoinflammatory disorder phenotype: an Italian case series. Clin Exp Rheumatol 31(3 Suppl 77):155-156.