NLRC4 inflammasomopathies

Abstract

Purpose of review The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD domain-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies. Recent findings Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and anti-interferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases. Summary The NLRC4 inflammasomopathies comprise a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often-fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.

HSC70 regulates cold-induced caspase-1 hyperactivation by an autoinflammation-causing mutant of cytoplasmic immune receptor NLRC4

“…NLRC4 is generally activated by pathogen associated molecular patterns (PAMPs) 10 , but certain point mutations result in its constitutive activation, inflammasome formation and caspase-1 activation leading to autoinflammatory diseases 24 . Through this study, we show that HSC70 and HSP70 chaperone proteins form a complex with NLRC4.…”

“…Gain-of-function mutations in NLRC4 cause auto-inflammatory disorders in humans 24 . Fig.1A shows a schematic indicating positions of various disease associated mutations in NLRC4 protein.…”

“…Mutations in NLRC4 [18][19][20][21][22][23][24] and some other cytoplasmic immune receptors like NLRP1 11,[25][26][27] , NLRP3 [28][29][30][31] and NLRP12 [32][33][34] cause autoinflammatory syndromes, which occur in the absence of any infection or autoimmunity. One of the mutants of NLRC4, H443P causes familial cold autoinflammatory syndrome (FCAS) in heterozygous individuals 18 .…”

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

“…All GoF mutations in NLRC4 lead to an increased tendency toward oligomerization and can activate the inflammasome spontaneously. AIFEC flares have been described to resemble the macrophage activation syndrome (MAS), as evidenced by a prominent IL‐1β signature, myeloid cell activation, cytotoxic T‐cell dysfunction and IFN gamma (IFNγ)‐related hemophagocytosis 203 . Distinctly, IL‐18 serum levels—that drive IFNγ production—and the IL‐18/CXCL9 ratio are highly elevated in AIFEC patients, even compared to NOMID patients, which is reminiscent of adult‐onset stills disease‐related MAS or X‐linked inhibitor of apoptosis deficiency (XIAP) 201,203,204 .…”

“…AIFEC flares have been described to resemble the macrophage activation syndrome (MAS), as evidenced by a prominent IL‐1β signature, myeloid cell activation, cytotoxic T‐cell dysfunction and IFN gamma (IFNγ)‐related hemophagocytosis 203 . Distinctly, IL‐18 serum levels—that drive IFNγ production—and the IL‐18/CXCL9 ratio are highly elevated in AIFEC patients, even compared to NOMID patients, which is reminiscent of adult‐onset stills disease‐related MAS or X‐linked inhibitor of apoptosis deficiency (XIAP) 201,203,204 . Since then, additional patients have been reported with either AD germline or somatic mutations in NLRC4 , with phenotypes similar to NOMID and FCAS syndromes 203‐205 .…”