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Arthritis Rheumatol. 2015 Feb;67(2):563-7.

Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation.

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.

PMID:
25418813
PMCID:
PMC4369162
DOI:
10.1002/art.38961
[Indexed for MEDLINE]
Free PMC Article

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