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Brief Report: Connecting Two Pathways Through Ca 2+ Signaling: NLRP3 Inflammasome Activation Induced by a Hypermorphic PLCG2 Mutation
Author(s) -
Chae Jae Jin,
Park Yong Hwan,
Park Chung,
Hwang IlYoung,
Hoffmann Patrycja,
Kehrl John H.,
Aksentijevich Ivona,
Kastner Daniel L.
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38961
Subject(s) - inflammasome , intracellular , endoplasmic reticulum , extracellular , microbiology and biotechnology , phospholipase c , pathogenesis , calcium in biology , signal transduction , calcium signaling , biology , chemistry , inflammation , immunology
Objective We previously reported that p.Ser707Tyr, a novel variant in phospholipase Cγ2 (PLCγ2), is the cause of a dominantly inherited autoinflammatory disease, autoinflammation and PLCγ2‐associated antibody deficiency and immune dysregulation (APLAID). The hypermorphic mutation enhances PLCγ2 activity and causes an increase in intracellular Ca 2+ release from endoplasmic reticulum stores. Because increased intracellular Ca 2+ signaling has been associated with NLRP3 inflammasome activation, we studied the role of the NLRP3 inflammasome in the pathogenesis of APLAID. Methods Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and 2 patients with APLAID. Inflammasome activation was analyzed by Western blotting. Intracellular Ca 2+ levels were measured with a FLIPR Calcium 4 assay kit. Results Cells from the patients had elevated basal levels of intracellular Ca 2+ , and the intracellular Ca 2+ flux triggered by extracellular CaCl 2 was substantially enhanced. Patient PBMCs secreted interleukin‐1β in response to lipopolysaccharide priming alone, and this effect was attenuated by treatment with a PLC inhibitor, intracellular Ca 2+ blockers, or an adenylate cyclase activator. Conclusion Our findings suggest that the inflammation in patients with APLAID is partially driven by activation of the NLRP3 inflammasome. These data link 2 seemingly distinct molecular pathways and provide new insights into the pathogenesis of APLAID and autoinflammation.