Brief Report: Connecting Two Pathways Through Ca2+ Signaling: NLRP3 Inflammasome Activation Induced by a Hypermorphic PLCG2 Mutation1. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Chae, Jae Jin; Park, Yong Hwan; Park, Chung; Hwang, Il‐Young; Hoffmann, Patrycja; Kehrl, John H.; Aksentijevich, Ivona; Kastner, Daniel L.
• Is Part Of: Arthritis & rheumatology. Volume 67:Issue 2(2015)
• Page Start: 563
• Page End: 567
• Publication Date: 2015-02
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.38961
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art38961-sec-0001" sec-type="section"> <title>Objective</title> <p>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<sup>2+</sup> release from endoplasmic reticulum stores. Because increased intracellular Ca<sup>2+</sup> signaling has been associated with NLRP3 inflammasome activation, we studied the role of the NLRP3 inflammasome in the pathogenesis of APLAID.</p> </sec> <sec id="art38961-sec-0002" sec-type="section"> <title>Methods</title> <p>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<sup>2+</sup> levels were measured with a FLIPR Calcium 4 assay kit.</p> </sec> <sec id="art38961-sec-0003" sec-type="section"> <title>Results</title> <p>Cells from the patients had elevated basal levels of intracellular Ca<sup>2+</sup>, and the intracellular Ca<sup>2+</sup> flux triggered by extracellular CaCl<sub>2</sub> 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<sup>2+</sup> blockers, or an adenylate cyclase activator.</p> </sec> <sec id="art38961-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>