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PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling

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2021

J Exp Med. 2021 Jun 7;218(6):e20210008. doi: 10.1084/jem.20210008.

PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling

Jiwen Li, Catharina Conrad, Tingting W Mills, Nathaniel K Berg, Boyun Kim, Wei Ruan, Jae W Lee, Xu Zhang, Xiaoyi Yuan, Holger K Eltzschig.

Department of Anesthesiology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX. Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany. Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX. Department of Anesthesiology, Second Xiangya Hospital, Central South University, Hunan, China. Department of Anesthesiology, Yale University School of Medicine, New Haven, CT. Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX.

Service type: Knockout mice

Abstract

Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1-elicited cardioprotection. These findings suggest an autocrine signaling loop with a functional role for neutrophil-derived netrin-1 in attenuating myocardial ischemia-reperfusion injury through myeloid adenosine A2b signaling.

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