The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
Guillaume Paré1, Julien Vitry1,2, Michael L Merchant3
1Division of Infectious Diseases and Immunology, Laval University, Centres Hospitaliers Universitaires (CHU) de Québec Research Center, Québec, QC, Canada.
Frontiers in Immunology
|July 8, 2021
Summary
The myeloid inhibitory receptor CLEC12A limits neutrophil activation. This study reveals CLEC12A signaling in human neutrophils involves Src-dependent ITIM phosphorylation and p38/Akt pathways, modulating cytokine release.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- The C-type lectin receptor CLEC12A inhibits neutrophil activation but its molecular mechanism is unclear.
- Understanding CLEC12A signaling is crucial for inflammatory disease therapies.
Purpose of the Study:
- To elucidate the early molecular events of CLEC12A-mediated inhibitory signaling in human neutrophils.
- To investigate how CLEC12A counteracts activating signals, particularly in response to uric acid crystals.
Main Methods:
- Cross-linking of CLEC12A in human neutrophils.
- Analysis of CLEC12A translocation to membrane domains.
- Phosphoproteomic analysis to identify downstream signaling molecules.
- Stimulation with uric acid crystals and measurement of cytokine release (IL-8).
Main Results:
- CLEC12A cross-linking induced its translocation to flotillin-rich domains and ITIM phosphorylation dependent on Src kinase.
- Phosphoproteomic analysis identified MAPKs, phosphoinositol kinases, and JAK-STAT pathway members as regulated by CLEC12A.
- Uric acid crystal stimulation led to hyperphosphorylation of p38 and Akt.
- CLEC12A signaling modulates uric acid crystal-induced IL-8 release via a p38/PI3K-Akt pathway.
Conclusions:
- This study defines key molecular events in CLEC12A signaling in human neutrophils.
- CLEC12A regulates cytokine synthesis, specifically IL-8 release, through the p38/PI3K-Akt pathway in response to uric acid crystals.
- Targeting CLEC12A signaling offers a potential therapeutic strategy for dampening inflammation.
Keywords:
C-type lectin inhibitory receptorCLEC12A proteinMAPKgoutinflammationneutrophilrheumatoid arthritissignaling/signaling pathwaysMore Related Videos
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