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 Article has an altmetric score of 16

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 7

Divergent roles for AXL and MerTK in cardiac repair after myocardial ischemia/reperfusion infarction (IRI).

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Divergent roles for AXL and MerTK in cardiac repair after myocardial isc...
(A) Phagocytosis of apoptotic mCherry-expressing cardiomyocytes by cardiac macrophages from Axl+/+ or Axl–/– mice at baseline (Ø) or 4 hours after IRI. n = 3–5 mice/group pooled from 3 independent experiments. *P < 0.05 by 2-way ANOVA followed by Tukey’s test. (B) Percentage infarct/left ventricle (LV), percentage area at risk (AAR)/LV, and percentage infarct/AAR measured 7 days after IRI in mice lacking Mertk (Axl+/+ Mertk–/–), Axl (Axl–/– Mertk+/+), or both Mertk and Axl (Axl–/– Mertk–/–). n = 6–9 mice/group pooled from more than 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by Tukey’s test. (C) Expression of MerTK and AXL on cardiac macrophages from Axl- or Mertk-deficient mice as measured 3 days after IRI. n = 4–5 mice/group pooled from 2 independent experiments. NS, not significant by 2-tailed, unpaired t test. (D) Quantification of percentage ejection fraction (% EF) in mice 28 days after IRI. n = 4 mice/group pooled from 4 independent experiments. *P < 0.05, ***P < 0.001 by 1-way ANOVA followed by Tukey’s test. (E) Ratio of MHCIIlo to MHCIIhi cardiac macrophages within the infarcted myocardium of Axl+/+ Mertk+/+ or Axl–/– Mertk–/– mice. n = 3–5 mice/group pooled from 3 independent experiments. ***P < 0.001 by 2-way ANOVA followed by Tukey’s test. (F) Infarct measurements 7 days after IRI in Mertk+/+ or MertkCR/CR mice treated with the AXL-selective inhibitor R428 or vehicle. n = 3–4 mice/group pooled from 3 independent experiments. **P < 0.01, ***P < 0.001 by 2-way ANOVA followed by Tukey’s test. (G) Infarct measurements 7 days after IRI in Mertk–/– mice treated with the AXL-selective inhibitor R428 or vehicle. n = 5–7 mice/group pooled from 3 independent experiments. **P < 0.01 by 2-tailed, unpaired t test. All data presented as mean ± SEM.