Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction
Matthew DeBerge, … , Ira Tabas, Edward B. Thorp
Matthew DeBerge, … , Ira Tabas, Edward B. Thorp
Published February 2, 2021
Citation Information: J Clin Invest. 2021;131(6):e139576. https://doi.org/10.1172/JCI139576.
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Research Article Cardiology Inflammation

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction

Abstract

Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. Although the role of MerTK in cardioprotection is well characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically relevant models of myocardial ischemia/reperfusion infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a maladaptive role for myeloid AXL during IRI in the heart. Cross signaling between AXL and TLR4 in cardiac macrophages directed a switch to glycolytic metabolism and secretion of proinflammatory IL-1β, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function. AXL functioned independently of cardioprotective MerTK to reduce the efficacy of cardiac repair, but like MerTK, was proteolytically cleaved. Administration of a selective small molecule AXL inhibitor alone improved cardiac healing, which was further enhanced in combination with blockade of MerTK cleavage. These data support further exploration of macrophage TAM receptors as therapeutic targets for myocardial infarction.

Authors

Matthew DeBerge, Kristofor Glinton, Manikandan Subramanian, Lisa D. Wilsbacher, Carla V. Rothlin, Ira Tabas, Edward B. Thorp

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Figure 2

Macrophage AXL worsens cardiac repair after myocardial ischemia/reperfusion infarction (IRI).

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Macrophage AXL worsens cardiac repair after myocardial ischemia/reperfus...
(A) Representative 1-mm heart sections from an individual Axl+/+ or Axl–/– mouse 7 days after IRI stained with triphenyltetrazolium chloride (TTC) for infarct measurements or injected with fluorescent microspheres to quantify the area at risk (AAR). From left to right, apex toward the ligation site. Percentage infarct/left ventricle (LV), percentage AAR/LV, and percentage infarct/AAR measured 7 days after IRI in mice with whole-body deletion of Axl. n = 7–9 mice/group pooled from 3 independent experiments. *P < 0.05, **P < 0.01 by 2-tailed, unpaired t test. (B) Representative B-mode and M-mode echocardiography images of systole and diastole in hearts 21 days after IRI with quantification of percentage ejection fraction (% EF), percentage fractional shortening (% FS), systolic and diastolic volume, LV wall thickness, internal diameter, and LV mass 21 days after IRI. n = 5–9 mice/group pooled from 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-way ANOVA followed by Tukey’s test. (C) AXL expression on cardiac macrophages in mice with myeloid-specific deletion of Axl (LysM-Cre+ Axlfl/fl) as measured by flow cytometry. Data are representative of 2 independent experiments. n = 3 mice/group. *P < 0.05 by 2-tailed, unpaired t test. (D) Infarct measurements 7 days after IRI in LysM-Cre+ Axlfl/fl mice compared with LysM-Cre– Axlfl/fl littermate controls. n = 5–6 mice/group pooled from 2 independent experiments. *P < 0.05 by 2-tailed, unpaired t test. All data presented as mean ± SEM.