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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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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. |
format | Online Article Text |
id | pubmed-8256872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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