Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms

Singh, Brenal K.; Lu, Wen; Paustian, Amanda M. Schmidt; Ge, Moyar Q.; Koziol‐White, Cynthia; Flayer, Cameron H.; Killingbeck, Sara S.; Wang, Nadan; Dong, Xinzhong; Riese, Matthew J.; Deshpande, Deepak A.; Panettieri, Reynold A.; Haczku, Angela Franciska; Kambayashi, Taku

doi:10.1126/scisignal.aax3332

Cited by 24 publications

(17 citation statements)

References 82 publications

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“…Additional analysis showed higher expression of perforin and granzymes A, B and C as well as IL-2 and TNFα, with reduction in TGFβ expression ( Figure 1C). Greater IFN-γ and TNFα expression correlates well with the enhanced skewing toward Th1 phenotypes that results from DGKζ deficiency, 22 and resembles the increased levels of circulating IFNγ in AA patients. 23 Augmented expression of granzymes B and C and perforin in DGKζ -/mouse BM denotes an increase in cytotoxic T cells (CTL) similar to that described in AA patients.…”

Section: Resultsmentioning

confidence: 75%

“…44 This promotes a CD4 Th1/ Th2 skew that provides DGKζ -/mice with enhanced anti-viral responses, 5 granting protection against allergic asthma. 22 DGKζ deficiency also potentiates cytotoxic programs in CD8 + T and NK cells, boosting antitumor functions in an antigen-dependent 45 and -independent manner. 6,46 These and other studies CD69 is an activation marker that is induced rapidly after antigen recognition and decays very rapidly in peripheral cells.…”

Section: Discussionmentioning

confidence: 99%

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Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Martin-Salgado¹,

Andrada

Liébana³

et al. 2020

Preprint

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Key points• DGKζ-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFNγ and lytic enzymes.• DGKζ loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. Visual abstractAbstract Acquired aplastic anemia (AA) is a rare blood disorder that results from immune-mediated destruction of bone marrow (BM) progenitor cells. Improved understanding of the mechanisms that favor T cell attack in BM could help to improve early diagnosis and disease treatment. Diacylglycerol kinase ζ (DGKζ) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKCθ/NFκB pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGKζ -/mice showed increased numbers of activated T cells in BM, together with a significant increase in IFNγ as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGKζ -/mouse BM correlates with reduced BM cellularity, impaired hematopoiesis, and lower frequency of circulating red cells, granulocytes, and platelets. Our studies coincide with the recent characterization of lower DGKζ expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGKζ expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGKζ deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development.

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Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Martin-Salgado¹,

Andrada

Liébana³

et al. 2020

Preprint

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“…The targeted deletion of DGKζ in the T cells decreases type 2 inflammation without reducing airway hyperresponsiveness (AHR). However, the loss of DGKζ in the airway smooth muscle cells decreases AHR but not airway inflammation [204]. DGKζ was reported to limit the inflammatory cytokine production and pro-inflammatory M1-like macrophage polarization through the downregulation of STAT1 and STAT3 phosphorylation in the cytokine storm syndrome mouse model, which was dependent on TLR9 signaling, and the arthritic mouse model, which was dependent on TLR2 signaling [205].…”

Section: Inflammation and Immunitymentioning

confidence: 99%

Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling

Sim

Kim

Yang

2020

IJMS

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The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the mammalian cells. Studies on the regulation of diacylglycerol and phosphatidic acid levels by various enzymes, the identification and characterization of various diacylglycerol and phosphatidic acid-regulated proteins, and the overlap of different diacylglycerol and phosphatidic acid metabolic and signaling processes have revealed the complex and non-redundant roles of diacylglycerol kinases in regulating multiple biochemical and biological networks. In this review article, we summarized recent progress in the complex and non-redundant roles of diacylglycerol kinases, which is expected to aid in restoring dysregulated biochemical and biological networks in various pathological conditions at the bed side.

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“…Recently, targeting the diacylglycerol metabolism by DGKζ knockdown or treatment with the DGKα-specific inhibitor R59949 has proven to be beneficial for treating asthma by reducing both inflammation and airway hyperresponsiveness [127]. Ongoing studies are evaluating the impact of DGKα inhibitors in the context of α1-antitrypsin mutations that result in 1AAD.…”

Section: Dgks In Respiratory Diseasesmentioning

confidence: 99%

DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases

Baldanzi

Malerba

2019

IJMS

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Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGKα and DGKζ as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGKα, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGKα activation is necessary for migration and a productive response. The role of DGKα in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGKα transcript. Together with in vitro experiments, this suggests that DGKs may represent potential therapeutic targets for disorders where inflammation, and neutrophils in particular, plays a major role. In this paper we focus on obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), but also rare genetic diseases such as alpha-1-antitrypsin deficiency. Indeed, the biological role of DGKα is understudied outside the T lymphocyte field. The recent wave of research aiming to develop novel and specific inhibitors as well as KO mice will allow a better understanding of DGK’s role in neutrophilic inflammation. Better knowledge and pharmacologic tools may also allow DGK to move from the laboratory bench to clinical trials.

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Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms

Cited by 24 publications

References 82 publications

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling

DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases

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