Hypoxia/ischemia promotes CXCL10 expression in cardiac microvascular endothelial cells by NFkB activation

Xia, Jing; Liu, Guang Hui; Chen, Zhuo Ying; Mao, Cheng Zhou; Zhou, Deng Cheng; Wu, Hai Yan; Park, Kyu Sang; Zhao, Hui; Kim, Soo Ki; Cai, Dongqing; Qi, Xu

doi:10.1016/j.cyto.2016.02.007

Cited by 41 publications

(29 citation statements)

References 28 publications

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“…and CXCL11 (19). CXCL10, a factor determined to have the highest predictive value for early cardiac acute rejection (20), was initially reported to be induced by IFN-γ and secreted by various cell types, including monocytes, neutrophils, endothelial cells, keratinocytes and fibroblasts (21,22). After the first transplantation, CXCL10 was released into the circulation and recognized by CXCR3, which was expressed on the surface of Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Deng

et al. 2017

Exp Ther Med

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Abstract. The interaction of chemokine (C-X-C motif) ligand 10 (CXCL10) with its receptor (CXCR3) is a critical process in recruiting donor reactive T cells to a graft and alloantigen-specific memory T (Tm) cells exert a principal function in promoting graft dysfunction during accelerated cardiac rejection. However, whether CXCL10 chemokine exerts any effects on acute accelerated rejection mediated by CD8 + Tm cells in a re-transplant model has remained elusive. The present study established a cardiac transplant model by advanced microsurgery technology and improved organ storage. A novel rat model of cardiac re-transplantation was established at 40 days following primary heart transplant. The experiment included two parts, and when models were established, the rats were divided into two groups: Primary cardiac transplant (HTx) and re-transplantation without treatment (HRTx). In part 1, recipients from part 2, including re-transplantation without treatment (HRTx+NS) and re-transplantation treated with anti-CXCL10 antibodies (500 µg every other day by intraperitoneal injection; HRTx+CXCL10 Abs group). The graft survival time was observed and graft infiltration by inflammatory cells was assessed via histology of cardiac graft sections; in addition, the gene expression and the serum concentration of CXCL10 in each group was assessed. Indexes such as rejection-associated cytokines were assayed by reverse-transcription quantitative PCR and ELISA kits, and flow cytometry of splenocytes was used to detect Tm cells in the re-transplantation groups. The results demonstrated that level of CXCL10 was significantly increased and the graft mean survival time was shortened accompanied with aggravated lymphocyte cell infiltration in the HRTx group when compared that in the HTx group; in addition, the serum levels and mRNA expression of interleukin (IL)-2 and interferon (IFN)-γ were increased, while transforming growth factor (TGF)-β was decreased in the HRTx group. Furthermore, neutralization of CXCL10 prolonged the graft mean survival time and delayed accelerated rejection. Compared with that in the HRTx+NS group, serum levels and graft tissue mRNA expression of IFN-γ and IL-2 were decreased in the HRTx+CXCL10 Abs group, while TGF-β mRNA was significantly increased but the serum concentration was not significantly affected. In addition, there was no difference in IL-10 between the two groups, while delayed accelerated rejection paralleled with inflammatory cell infiltration decreased and the proliferation and differentiation of CD8 + Tm cells in secondary lymphoid organs were reduced in the HRTx+CXCL10 Abs group vs. those in the HRTx+NS group. The present study demonstrated that CXCL10 had a crucial role in cardiac transplantation and re-transplantation, and that treatment with CXCL10 antibodies delays accelerated acute rejection mediated by Tm cells in a rat model of cardiac re-transplantation. IntroductionA multidisciplinary program has been initiated to better establish transplantation for prolonging survival time of cardi...

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Section: Discussionmentioning

confidence: 99%

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Deng

et al. 2017

Exp Ther Med

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“…After cells reached confluency, cells were exposed to normoxia (21% oxygen) or hypoxia (1% oxygen using preequilibrated media for 3 h [37]) and immediately resuspended in Trizol for miRNA analysis.…”

Section: Methodsmentioning

confidence: 99%

Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms

et al. 2017

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A wide search for ischemic preconditioning (IPC) mechanisms of cardioprotection identified the light elicited circadian rhythm protein Period 2 (Per2) to be cardioprotective. Studies on cardiac metabolism found a key role for light elicited Per2 in mediating metabolic dependence on carbohydrate metabolism. To profile Per2 mediated pathways following IPC of the mouse heart, we performed a genome array and identified 352 abundantly expressed and well-characterized Per2 dependent micro RNAs. One prominent result of our in silico analysis for cardiac Per2 dependent micro RNAs revealed a selective role for miR-21 in the regulation of hypoxia and metabolic pathways. Based on this Per2 dependency, we subsequently found a diurnal expression pattern for miR-21 with higher miR-21 expression levels at Zeitgeber time (ZT) 15 compared to ZT3. Gain or loss of function studies for miR-21 using miRNA mimics or miRNA inhibitors and a Seahorse Bioanalyzer uncovered a critical role of miR-21 for cellular glycolysis, glycolytic capacity, and glycolytic reserve. Exposing mice to intense light, a strategy to induce Per2, led to a robust induction of cardiac miR-21 tissue levels and decreased infarct sizes, which was abolished in miR-21-/- mice. Similarly, first translational studies in humans using intense blue light exposure for 5 days in healthy volunteers resulted in increased plasma miR-21 levels which was associated with increased phosphofructokinase activity, the rate-limiting enzyme in glycolysis. Together, we identified miR-21 as cardioprotective downstream target of Per2 and suggest intense light therapy as a potential strategy to enhance miR-21 activity and subsequent carbohydrate metabolism in humans.

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“…[10] In vitro, CXCL10 can also be induced by NF-kB, and has been shown to have an early role in hypoxia-induced inflammation. [18, 19] Activation of IFN-regulatory factor 3, toll-like receptors, retinoic acid-inducible gene (RIG)-I, and melanoma differentiation-associated gene (MDA)-5 work in synergy with IFNs for CXCL10 induction. [17, 20] Serum CXCL10 concentration, but not CXCL9, was reportedly correlated with the number of circulating lymphocytes in head and neck cancer with radiation therapy.…”

Section: The Expression and Implication Of Cxcl9 Cxcl10 Cxcl11 And mentioning

confidence: 99%

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

Tokunaga

Zhang

Naseem

et al. 2018

Cancer Treatment Reviews

1,020

779

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Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.

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Hypoxia/ischemia promotes CXCL10 expression in cardiac microvascular endothelial cells by NFkB activation

Cited by 41 publications

References 28 publications

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

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