CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

Mu, Yang; Zhang, Jinxue; Liu, Yongming; Ma, Jingchang; Jiang, Dongxu; Zhang, Xuexin; Yi, Xin; Cheng, Kun; Shen, Shen; Yang, Yixin; Zhuang, Ran; Zhang, Yuan

doi:10.1002/jlb.2ma1119-174rr

Cited by 21 publications

(12 citation statements)

References 47 publications

(86 reference statements)

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“…Several studies have demonstrated that a deficiency or blockade of DNAM-1 increases the numbers of Foxp3 + cells and enhances Treg cell function in mouse models of acute graft-versus-host disease (GVHD), unilateral ureteral obstruction, and allogeneic skin transplantation (18)(19)(20), suggesting that DNAM-1 suppresses, rather than enhances, Treg cell function. In sharp contrast, TIGIT promotes the production of anti-inflammatory cytokines, such as IL-10 and fibrinogen-like protein 2 (Fgl2), by Treg cells, thus suppressing Th1 and Th17 reactions (21) and suggesting that TIGIT is involved in the immune-suppressive function of Treg…”

mentioning

confidence: 99%

DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

Satoh

Yamashita-Kanemaru

Abe

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to their common ligand CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function without DNAM-1–mediated intracellular signaling. DNAM-1 deficiency augments TIGIT signaling; this subsequently inhibits activation of the protein kinase B–mammalian target of rapamycin complex 1 pathway, resulting in the maintenance of Foxp3 expression and Treg cell function under inflammatory conditions. These findings demonstrate that DNAM-1 regulates Treg cell function via TIGIT signaling and thus, it is a potential molecular target for augmenting Treg function in inflammatory diseases.

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confidence: 99%

DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

Satoh

Yamashita-Kanemaru

Abe

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Tek cre mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). CD226 fl/fl mice on a C57BL/6 background were generated by Cyagen Biosciences (Suzhou, China) 22 . Homozygous CD226 + (CD226 fl/fl ) mice were crossed with Tek cre mice to get CD226 fl/wt Tek cre mice that were then self‐crossed to obtain CD226 fl/fl Tek cre (CD226 conditional knockout [CKO]) and CD226 wt/wt Tek cre (wild‐type, WT) mice, which were identified by genotyping and immunofluorescence staining (as follow).…”

Section: Methodsmentioning

confidence: 99%

“…CD226 fl/fl mice on a C57BL/6 background were generated by Cyagen Biosciences (Suzhou, China). 22 Homozygous CD226 + (CD226 fl/fl ) mice were crossed with Tek cre mice to get CD226 fl/wt Tek cre mice that were then self-crossed to obtain CD226 fl/fl Tek cre (CD226 conditional knockout [CKO]) and CD226 wt/wt Tek cre (wild-type, WT) mice, which were identified by genotyping and immunofluorescence staining (as follow). For HS modeling, male C57BL/6 mice, aged 8-12 weeks and weighing 20-25 g, were randomly divided into HS and sham groups.…”

Section: Introductionmentioning

confidence: 99%

CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock

et al. 2021

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Hemorrhagic shock (HS) is common in clinical emergencies, leading to millions of deaths each year globally. CD226 is a costimulatory adhesion molecule expressed on both immune cells and endothelial cells (ECs) to regulate their metabolic activity and function. As endothelial dysfunction occurs after HS, the roles CD226 plays in vascular EC metabolism were investigated. CD226 fl/fl Tek cre mice were adopted to achieve vascular EC-specific knockout of CD226, and subjected to HS modelling. Serum levels of crucial intermediate metabolites were evaluated through liquid chromatography-mass spectrometry analysis. Human umbilical vein ECs (HUVECs) were used to study the effects of CD226 under hypoxia in vitro. Seahorse analysis evaluated the cellular glycolysis and mitochondria bioenergetics. Results showed that CD226 deficiency in vascular ECs alleviated HSinduced intestinal damage and inflammatory response in mice. Animal studies indicated an improved energy metabolism when CD226 was knocked out in ECs after HS, as evidenced by enhanced glutamine-glutamate metabolism and decreased lactic acid levels. Glut-1 was upregulated in mouse vascular ECs after HS and HUVECs under hypoxia, combined with decreased CD226. Moreover, HUVECs with CD226 knockdown exhibited relieved mitochondrial damage and early apoptosis under hypoxia, whereas CD226 overexpression showed opposite effects. Seahorse analysis showed that downregulated CD226 significantly increased mitochondrial ATP production and glucose uptake in HUVECs under hypoxia. Additionally, Erk/PHD2 signaling-mediated HIF-1α/Glut-1 and HIF-2α/

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“…The Treg-macrophage inhibitory interaction was transforming growth factor-β (TGF-β)-dependent (Mahajan et al, 2006 ). Besides that, CD226 deficiency on Tregs exacerbated renal fibrosis in the UUO model by upregulating Th2-related cytokines like IL-4 (Mu et al, 2020 ). Recently, a single-cell RNA sequencing study showed that tissue-resident IL-33R + and IL-2Ra + Tregs markedly increased following injury in the two mouse models of either kidney repair or fibrosis.…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Lymphocytes: Versatile Participants in Acute Kidney Injury and Progression to Chronic Kidney Disease

2021

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Background: Acute kidney injury (AKI) remains a major global public health concern due to its high morbidity and mortality. The progression from AKI to chronic kidney disease (CKD) makes it a scientific problem to be solved. However, it is with lack of effective treatments.Summary: Both innate and adaptive immune systems participate in the inflammatory process during AKI, and excessive or dysregulated immune responses play a pathogenic role in renal fibrosis, which is an important hallmark of CKD. Studies on the pathogenesis of AKI and CKD have clarified that renal injury induces the production of various chemokines by renal parenchyma cells or resident immune cells, which recruits multiple-subtype lymphocytes in circulation. Some infiltrated lymphocytes exacerbate injury by proinflammatory cytokine production, cytotoxicity, and interaction with renal resident cells, which constructs the inflammatory environment and induces further injury, even death of renal parenchyma cells. Others promote tissue repair by producing protective cytokines. In this review, we outline the diversity of these lymphocytes and their mechanisms to regulate the whole pathogenic stages of AKI and CKD; discuss the chronological responses and the plasticity of lymphocytes related to AKI and CKD progression; and introduce the potential therapies targeting lymphocytes of AKI and CKD, including the interventions of chemokines, cytokines, and lymphocyte frequency regulation in vivo, adaptive transfer of ex-expanded lymphocytes, and the treatments of gut microbiota or metabolite regulations based on gut-kidney axis.Key Message: In the process of AKI and CKD, T helper (Th) cells, innate, and innate-like lymphocytes exert mainly pathogenic roles, while double-negative T (DNT) cells and regulatory T cells (Tregs) are confirmed to be protective. Understanding the mechanisms by which lymphocytes mediate renal injury and renal fibrosis is necessary to promote the development of specific therapeutic strategies to protect from AKI and prevent the progression of CKD.

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CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

Cited by 21 publications

References 47 publications

DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock

Lymphocytes: Versatile Participants in Acute Kidney Injury and Progression to Chronic Kidney Disease

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