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- Title
Brief Report: Connecting Two Pathways Through Ca<sup>2+</sup> Signaling: NLRP3 Inflammasome Activation Induced by a Hypermorphic PLCG2 Mutation.
- Authors
Chae, Jae Jin; Park, Yong Hwan; Park, Chung; Hwang, Il‐Young; Hoffmann, Patrycja; Kehrl, John H.; Aksentijevich, Ivona; Kastner, Daniel L.
- Abstract
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 Ca2+ release from endoplasmic reticulum stores. Because increased intracellular Ca2+ 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 Ca2+ levels were measured with a FLIPR Calcium 4 assay kit. Results Cells from the patients had elevated basal levels of intracellular Ca2+, and the intracellular Ca2+ flux triggered by extracellular CaCl2 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 Ca2+ 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.
- Subjects
MARYLAND; GENETICS of autoimmune diseases; CALCIUM antagonists; ACADEMIC medical centers; CALCIUM; CELLULAR signal transduction; GENETIC mutation; RESEARCH funding; WESTERN immunoblotting; DATA analysis software; THERAPEUTICS
- Publication
Arthritis & Rheumatology, 2015, Vol 67, Issue 2, p563
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.38961