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The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release

The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation, pro-inflammatory pathways and disease in mouse models of inflammatory arthritis by a molecular mechanism that remains poorly understood. We addressed how CLEC12A-mediated inhibitory signaling counteracts activating s...

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Autores principales: Paré, Guillaume, Vitry, Julien, Merchant, Michael L., Vaillancourt, Myriam, Murru, Andréa, Shen, Yunyun, Elowe, Sabine, Lahoud, Mireille H., Naccache, Paul H., McLeish, Kenneth R., Fernandes, Maria J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256872/
https://www.ncbi.nlm.nih.gov/pubmed/34234773
http://dx.doi.org/10.3389/fimmu.2021.650808
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author Paré, Guillaume
Vitry, Julien
Merchant, Michael L.
Vaillancourt, Myriam
Murru, Andréa
Shen, Yunyun
Elowe, Sabine
Lahoud, Mireille H.
Naccache, Paul H.
McLeish, Kenneth R.
Fernandes, Maria J.
author_facet Paré, Guillaume
Vitry, Julien
Merchant, Michael L.
Vaillancourt, Myriam
Murru, Andréa
Shen, Yunyun
Elowe, Sabine
Lahoud, Mireille H.
Naccache, Paul H.
McLeish, Kenneth R.
Fernandes, Maria J.
author_sort Paré, Guillaume
collection PubMed
description The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation, pro-inflammatory pathways and disease in mouse models of inflammatory arthritis by a molecular mechanism that remains poorly understood. We addressed how CLEC12A-mediated inhibitory signaling counteracts activating signaling by cross-linking CLEC12A in human neutrophils. CLEC12A cross-linking induced its translocation to flotillin-rich membrane domains where its ITIM was phosphorylated in a Src-dependent manner. Phosphoproteomic analysis identified candidate signaling molecules regulated by CLEC12A that include MAPKs, phosphoinositol kinases and members of the JAK-STAT pathway. Stimulating neutrophils with uric acid crystals, the etiological agent of gout, drove the hyperphosphorylation of p38 and Akt. Ultimately, one of the pathways through which CLEC12A regulates uric acid crystal-stimulated release of IL-8 by neutrophils is through a p38/PI3K-Akt signaling pathway. In summary this work defines early molecular events that underpin CLEC12A signaling in human neutrophils to modulate cytokine synthesis. Targeting this pathway could be useful therapeutically to dampen inflammation.
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spelling pubmed-82568722021-07-06 The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release Paré, Guillaume Vitry, Julien Merchant, Michael L. Vaillancourt, Myriam Murru, Andréa Shen, Yunyun Elowe, Sabine Lahoud, Mireille H. Naccache, Paul H. McLeish, Kenneth R. Fernandes, Maria J. Front Immunol Immunology The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation, pro-inflammatory pathways and disease in mouse models of inflammatory arthritis by a molecular mechanism that remains poorly understood. We addressed how CLEC12A-mediated inhibitory signaling counteracts activating signaling by cross-linking CLEC12A in human neutrophils. CLEC12A cross-linking induced its translocation to flotillin-rich membrane domains where its ITIM was phosphorylated in a Src-dependent manner. Phosphoproteomic analysis identified candidate signaling molecules regulated by CLEC12A that include MAPKs, phosphoinositol kinases and members of the JAK-STAT pathway. Stimulating neutrophils with uric acid crystals, the etiological agent of gout, drove the hyperphosphorylation of p38 and Akt. Ultimately, one of the pathways through which CLEC12A regulates uric acid crystal-stimulated release of IL-8 by neutrophils is through a p38/PI3K-Akt signaling pathway. In summary this work defines early molecular events that underpin CLEC12A signaling in human neutrophils to modulate cytokine synthesis. Targeting this pathway could be useful therapeutically to dampen inflammation. Frontiers Media S.A. 2021-06-21 /pmc/articles/PMC8256872/ /pubmed/34234773 http://dx.doi.org/10.3389/fimmu.2021.650808 Text en Copyright © 2021 Paré, Vitry, Merchant, Vaillancourt, Murru, Shen, Elowe, Lahoud, Naccache, McLeish and Fernandes https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Paré, Guillaume
Vitry, Julien
Merchant, Michael L.
Vaillancourt, Myriam
Murru, Andréa
Shen, Yunyun
Elowe, Sabine
Lahoud, Mireille H.
Naccache, Paul H.
McLeish, Kenneth R.
Fernandes, Maria J.
The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
title The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
title_full The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
title_fullStr The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
title_full_unstemmed The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
title_short The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
title_sort inhibitory receptor clec12a regulates pi3k-akt signaling to inhibit neutrophil activation and cytokine release
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256872/
https://www.ncbi.nlm.nih.gov/pubmed/34234773
http://dx.doi.org/10.3389/fimmu.2021.650808
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