PMID- 34804012
OWN - NLM
STAT- MEDLINE
DCOM- 20220107
LR  - 20240509
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Loss of Diacylglycerol Kinase alpha Enhances Macrophage Responsiveness.
PG  - 722469
LID - 10.3389/fimmu.2021.722469 [doi]
LID - 722469
AB  - 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, DGKalpha 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 DGKalpha. 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 DGKalpha in macrophages with potential 
      implications for wound healing, cancer therapy, and other settings.
CI  - Copyright (c) 2021 Manigat, Granade, Taori, Miller, Vass, Zhong, Harris and Purow.
FAU - Manigat, Laryssa C
AU  - Manigat LC
AD  - Department of Pathology, School of Medicine, University of Virginia, 
      Charlottesville, VA, United States.
FAU - Granade, Mitchell E
AU  - Granade ME
AD  - Department of Pharmacology, School of Medicine, University of Virginia, 
      Charlottesville, VA, United States.
FAU - Taori, Suchet
AU  - Taori S
AD  - Department of Neurology, Division of Neuro-Oncology, University of Virginia, 
      Charlottesville, VA, United States.
FAU - Miller, Charlotte Anne
AU  - Miller CA
AD  - Department of Neurology, Division of Neuro-Oncology, University of Virginia, 
      Charlottesville, VA, United States.
FAU - Vass, Luke R
AU  - Vass LR
AD  - Department of Pathology, School of Medicine, University of Virginia, 
      Charlottesville, VA, United States.
FAU - Zhong, Xiao-Ping
AU  - Zhong XP
AD  - Division of Allergy and Immunology, Department of Pediatrics, Duke University 
      Medical Center, Durham, NC, United States.
FAU - Harris, Thurl E
AU  - Harris TE
AD  - Department of Pharmacology, School of Medicine, University of Virginia, 
      Charlottesville, VA, United States.
FAU - Purow, Benjamin W
AU  - Purow BW
AD  - Department of Neurology, Division of Neuro-Oncology, University of Virginia, 
      Charlottesville, VA, United States.
LA  - eng
GR  - P30 CA044579/CA/NCI NIH HHS/United States
GR  - R01 CA180699/CA/NCI NIH HHS/United States
GR  - R01 CA189524/CA/NCI NIH HHS/United States
GR  - R01 GM136900/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211105
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - EC 2.7.1.107 (Diacylglycerol Kinase)
SB  - IM
MH  - Animals
MH  - Diacylglycerol Kinase/genetics/*metabolism
MH  - Disease Models, Animal
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neoplasms/metabolism
MH  - T-Lymphocytes/*cytology/immunology
PMC - PMC8603347
OTO - NOTNLM
OT  - BMDM
OT  - DGKalpha
OT  - diacylglycerol kinase
OT  - immune regulation
OT  - macrophage
OT  - wound healing
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/11/23 06:00
MHDA- 2022/01/08 06:00
PMCR- 2021/01/01
CRDT- 2021/11/22 06:41
PHST- 2021/06/08 00:00 [received]
PHST- 2021/10/21 00:00 [accepted]
PHST- 2021/11/22 06:41 [entrez]
PHST- 2021/11/23 06:00 [pubmed]
PHST- 2022/01/08 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.722469 [doi]
PST - epublish
SO  - Front Immunol. 2021 Nov 5;12:722469. doi: 10.3389/fimmu.2021.722469. eCollection 
      2021.