Phospholipase Cγ-2 and Intracellular Calcium Are Required for Lipopolysaccharide-induced Toll-like Receptor 4 (TLR4) Endocytosis and Interferon Regulatory Factor 3 (IRF3) Activation
Open accessAbstract
Toll-like receptor 4 (TLR4) is unique among the TLRs in its use of multiple adaptor proteins leading to activation of both the interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) pathways. Previous work has demonstrated that TLR4 initiates NF-κB activation from the plasma membrane, but that subsequent TLR4 translocation to the endosomes is required for IRF3 activation. Here we have characterized several components of the signaling pathway that governs TLR4 translocation and subsequent IRF3 activation. We find that phospholipase C γ2 (PLCγ2) accounts for LPS-induced inositol 1,4,5-trisphosphate (IP(3)) production and subsequent calcium (Ca(2+)) release. Blockage of PLCγ2 function by inhibitors or knockdown of PLCγ2 expression by siRNAs in RAW 264.7 macrophages lead to reduced IRF3, but enhanced NF-κB activation. In addition, bone marrow-derived macrophages from PLCγ2-deficient mice showed impaired IRF3 phosphorylation and expression of IRF3-regulated genes after LPS stimulation. Using cell fractionation, we show that PLCγ2-IP(3)-Ca(2+) signaling cascade is required for TLR4 endocytosis following LPS stimulation. In conclusion, our results describe a novel role of the PLCγ2-IP(3)-Ca(2+) cascade in the LPS-induced innate immune response pathway where release of intracellular Ca(2+) mediates TLR4 trafficking and subsequent activation of IRF3.
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LPS-induced secretion of TNFα and other inflammatory cytokines is not affected in the absence of PLCγ2.
“As such, our results are in line with the observation that LPS-induced secretion of TNFα and other inflammatory cytokines is not affected in the absence of PLCγ2.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [45]
In “Intracellular Calcium Regulates LPS-induced ISG Expression” (page not provided), the paper reports that PLCγ2-knockout macrophages produced more TNFα after LPS stimulation, not an unaffected amount. It also reports similar or slightly higher expression of some inflammatory cytokine genes, but gene expression does not establish that their secretion was unaffected. (LLM, conf=0.87)
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Experimental — accuracy not yet measuredPrior work shows that loss of PLCγ2 can increase NF-κB signaling while reducing activation of the IRF3 pathway in PLCγ2-deficient macrophages.
“prior work showing that loss of PLCγ2 can increase NF-κB signaling while reducing activation of the interferon regulatory factor 3 (IRF3) pathway in PLCγ2-deficient macrophages [75]”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [75]
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- Authors
- Chiang, C.-Y., Veckman, V., Limmer, K., & David, M.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- David, Michael
- ORCID
- David, Michael
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 287
- Issue
- 6
- Pages
- 3704-3709
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3281733
- OpenAlex
- W2018306937
- Cited by
- 120
- References
- 27
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 8 · 2021: 11 · 2020: 9 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 11 · 2015: 12 · 2014: 8 · 2013: 6 · 2012: 8
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI047182)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- PLCγ2, TLR4, lipopolysaccharide, IRF3 activation, intracellular calcium, inositol 1,4,5-trisphosphate, NF-κB activation, macrophages, innate immunity
- MeSH terms
- Animals, Calcium, Cell Line, Endocytosis, Immunity, Innate, Lipopolysaccharides, Macrophages, Inositol 1,4,5-Trisphosphate, Calcium Signaling, Protein Transport, Interferon Regulatory Factor-3, Toll-Like Receptor 4, Mice, Phospholipase C gamma
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