An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

By S. Canna, A. D. de Jesus, Sushanth Gouni, S. Brooks, B. Marrero, Yin Liu, M. DiMattia, K. Zaal, Gina A. Montealegre Sanchez, Hanna Kim and 13 more. Nature Genetics, 2014

647 citations recorded by the source corpus.

Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1–blocking agents. Herein we report a de novo missense mutation (c.1009A>T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4–transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.

Subfields: Hematology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/07dd6337e5480357f46386708f83686121c704db

How researchers see this paper

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In Hematology

1. M. Lamkanfi
2. T. Kanneganti
3. Edward A. Miao

In Immunology

1. T. Kanneganti
2. M. Lamkanfi
3. Edward A. Miao
4. S. Man
5. Miriam Merad
6. B. Rollins

In Molecular Biology

1. T. Kanneganti
2. S. Man
3. M. Lamkanfi
4. D. Sharma
5. Edward A. Miao
6. Ine Jorgensen
7. F. Janku
8. N. Van Opdenbosch

Citations in the corpus

• Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. (2016, background): “Primary HLH is associated with several Mendelian inherited immune disorders, most of which induce impairment(86) (Table 5; supplemental Table 1) or disturbance of the inflammasome.(87,88)However, a proportion of suspected primary cases await molecular definition.”
• Pyroptotic cell death defends against intracellular pathogens (2015, background): “However, we must keep in mind that two of these mutations are very mild (threonine to serine, and valine to alanine) (111, 112), while the third appears to be autoactivated only upon exposure to cold temperatures (113).”
• Regulation of inflammasome activation (2015, background): “The patient with MAS responded to anakinra (162), suggesting that recombinant IL-1 receptor antagonist therapy could be used to treat those with autoinflammatory diseases associated with excessive NLRC4 inflammasome activation.”
• The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation (2016, background): “Human genetic studies have identified gain-of-function mutations in NLRC4 that are associated with autoinflammation and enterocolitis (Canna et al., 2014; Kitamura et al., 2014; Romberg et al., 2014).”
• Caspases in cell death, inflammation and disease (2019, background): “Indeed, an infant with life-threatening NLRC4associated hyperinflammation that was diagnosed with MAS has been effectively treated with recombinant IL-18 binding protein whereas anti-IL-1β and anti-TNF therapies had been unsuccessful (Canna et al., 2017).”