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

Author:

Li Jiwen12ORCID,Conrad Catharina13ORCID,Mills Tingting W.4ORCID,Berg Nathaniel K.1ORCID,Kim Boyun1ORCID,Ruan Wei15ORCID,Lee Jae W.6ORCID,Zhang Xu7ORCID,Yuan Xiaoyi1ORCID,Eltzschig Holger K.1ORCID

Affiliation:

1. Department of Anesthesiology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX

2. Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

3. Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany

4. Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX

5. Department of Anesthesiology, Second Xiangya Hospital, Central South University, Hunan, China

6. Department of Anesthesiology, Yale University School of Medicine, New Haven, CT

7. Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX

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.

Funder

National Institutes of Health

U.S. Department of Defense

Deutsche Forschungsgemeinschaft

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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