Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness

The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including gl...

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Autores principales:	Laryssa C. Manigat, Mitchell E. Granade, Suchet Taori, Charlotte Anne Miller, Luke R. Vass, Xiao-Ping Zhong, Thurl E. Harris, Benjamin W. Purow
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	DGKα diacylglycerol kinase macrophage immune regulation BMDM wound healing Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/5ba88728e8134ec2bb0acf93d24cdecf
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spelling	oai:doaj.org-article:5ba88728e8134ec2bb0acf93d24cdecf2021-11-05T15:14:36ZLoss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness1664-322410.3389/fimmu.2021.722469https://doaj.org/article/5ba88728e8134ec2bb0acf93d24cdecf2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.722469/fullhttps://doaj.org/toc/1664-3224The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.Laryssa C. ManigatMitchell E. GranadeSuchet TaoriCharlotte Anne MillerLuke R. VassXiao-Ping ZhongThurl E. HarrisBenjamin W. PurowFrontiers Media S.A.articleDGKαdiacylglycerol kinasemacrophageimmune regulationBMDMwound healingImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DGKα diacylglycerol kinase macrophage immune regulation BMDM wound healing Immunologic diseases. Allergy RC581-607
spellingShingle	DGKα diacylglycerol kinase macrophage immune regulation BMDM wound healing Immunologic diseases. Allergy RC581-607 Laryssa C. Manigat Mitchell E. Granade Suchet Taori Charlotte Anne Miller Luke R. Vass Xiao-Ping Zhong Thurl E. Harris Benjamin W. Purow Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
description	The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.
format	article
author	Laryssa C. Manigat Mitchell E. Granade Suchet Taori Charlotte Anne Miller Luke R. Vass Xiao-Ping Zhong Thurl E. Harris Benjamin W. Purow
author_facet	Laryssa C. Manigat Mitchell E. Granade Suchet Taori Charlotte Anne Miller Luke R. Vass Xiao-Ping Zhong Thurl E. Harris Benjamin W. Purow
author_sort	Laryssa C. Manigat
title	Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
title_short	Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
title_full	Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
title_fullStr	Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
title_full_unstemmed	Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
title_sort	loss of diacylglycerol kinase α enhances macrophage responsiveness
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/5ba88728e8134ec2bb0acf93d24cdecf
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Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness

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