Brief Report: Connecting Two Pathways Through Ca2+ Signaling: NLRP3 Inflammasome Activation Induced by a Hypermorphic PLCG2 Mutation
Open accessAbstract
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.
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IP3 triggers calcium release and DAG activates PKC and other effector proteins, influencing microglial processes such as migration, phagocytosis, cytokine secretion, and metabolic responses.
“IP3 triggers calcium release from intracellular stores, while DAG activates protein kinase C (PKC) and other effector proteins, ultimately influencing microglial processes such as migration, phagocytosis, cytokine secretion, and metabolic responses. 13 , 16 , 17”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [16]
The Introduction (page unavailable) states that InsP3 releases calcium from ER stores and identifies DAG as another product of PLCγ2. The Discussion (page unavailable) says PLCγ2 signaling includes PKC, but does not specifically link DAG to PKC or address other effector proteins. The Results concern IL-1β secretion from human PBMCs, not migration, phagocytosis, cytokine secretion, or metabolic responses in microglia. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPLCγ2 activation leads to an increase in cytoplasmic calcium, that supports the assembly of the NLRP3 inflammasome, and pro-inflammatory cytokine release in human blood monocytes, bone-marrow-derived macrophages and dendritic cells.
“PLCγ2 activation leads to an increase in cytoplasmic calcium, that supports the assembly of the pyrin (PYD)-domain-containing protein 3 (NLRP3) inflammasome, and pro-inflammatory cytokine release in human blood monocytes [31], bone-marrow-derived macrophages (BMDM) and dendritic cells [32].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [31]
The Results (page unavailable) link PLC-mediated calcium signaling to NLRP3 activation and IL-1β secretion in human peripheral blood mononuclear cells (PBMCs). The Methods (page unavailable) confirm that PBMCs, not isolated blood monocytes, were studied, so the claim is more cell-specific than this source supports. The macrophage and dendritic-cell portion is attached to a different citation [32] and is not assessed here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDAG leads to activation of protein kinase C (PKC) isozymes, the NLRP3 inflammasome, as well as other proteins.
“and DAG leading to activation of protein kinase C (PKC) isozymes, the NLRP3 inflammasome [31, 34], as well as other proteins [77].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [31]
The Introduction says PLCγ2 produces DAG and InsP3, and the Discussion says PLCγ2 can trigger protein kinase C signaling. The Results link NLRP3 inflammasome activation to the PLC–InsP3–Ca2+ pathway, not to DAG; the paper therefore does not support the claimed DAG-to-NLRP3 link. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA significant gain of function of PLCγ2 can lead to deleterious impacts on the immune system.
“These clearly indicate that a significant gain of function of PLCγ2 can lead to deleterious impacts on the immune system.”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [36]
Blood mononuclear cells from APLAID patients secreted increased levels of IL-1β.
“The inflammation found in APLAID has partially been attributed to the activation of the NLRP3 inflammasome as patient’s blood mononuclear cells secreted increased levels of IL-1β (109).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [109]
The inflammation found in APLAID has partially been attributed to activation of the NLRP3 inflammasome.
“The inflammation found in APLAID has partially been attributed to the activation of the NLRP3 inflammasome as patient’s blood mononuclear cells secreted increased levels of IL-1β (109).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [109]
Some effects of PLCγ2 GOF might be mediated via the activation of the NLRP3 inflammasome.
“some of the effects of PLCγ2 GOF might be mediated via the activation of the NLRP3 inflammasome [31, 100]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [31]
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- Authors
- Chae, J. J., Park, Y. H., Park, C., Hwang, I., Hoffmann, P., Kehrl, J. H., Aksentijevich, I., & Kastner, D. L.
- Affiliations
- National Institutes of Health (US)
- National Institute of Allergy and Infectious Diseases (US)
- ORCID
- Venue
- Arthritis & Rheumatology
- Publisher
- Wiley
- Published
- 2015-01-28
- Volume
- 67
- Issue
- 2
- Pages
- 563-567
- ISSN
- 2326-5191 (ISSN-L)
- 2326-5205
- PMC
- PMC4369162
- OpenAlex
- W1545536889
- Cited by
- 89
- References
- 12
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 12 · 2020: 15 · 2019: 8 · 2018: 9 · 2017: 6 · 2016: 2 · 2015: 2
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arthritis & Rheumatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 HG999999)
- National Human Genome Research Institute
- National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- NLRP3 inflammasome, autoinflammatory disease, intracellular calcium signaling, endoplasmic reticulum calcium release, interleukin-1β secretion, lipopolysaccharide, PLCγ2, adenylate cyclase, peripheral blood mononuclear cells
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Calcium, Calcium Channel Blockers, Carrier Proteins, Endoplasmic Reticulum, Humans, Immunologic Deficiency Syndromes, Immune System Diseases, Leukocytes, Mononuclear, Lipopolysaccharides, Mutation, Signal Transduction, Case-Control Studies, Calcium Signaling, Phospholipase C gamma, Interleukin-1beta, Inflammasomes
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