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. While 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-reperfused 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 unique 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.

Landscape of Cell Communication in Human Dental Pulp

“…[ 8 ] Pulp cells regulated the bactericidal activity of macrophages through LGALS9 and maintained their activity through AXL, CMKLR1, and TNFRSF1A. [ 9–11 ] Macrophages regulated the differentiation of DPSCs through EPHA3, NOTCH3, and GRN and received signals from DPSCs through ACVR, BMR1A, and BMR1B. The communication between macrophages and endothelial cells was similar to the communication between macrophages and DPSCs, except that CCR1, CX3CR1, CXCR1, IL15, and IL1ß were involved.…”

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

“…Of note, AXL sufficient MΦ promoted enhanced glycolysis to compensate for the energy demands needed for sustaining the pro-inflammatory state in response to infection induced inflammatory stimuli. This glycolytic reprogramming that occurs inside cardiac MΦ is dependent on hypoxia inducible factor-1 alpha (HIF-1α) [ 23 ]. Both HIF-1α signaling and IL-1β production are independently achieved through the phosphorylation of STAT-1 activation that is promoted by AXL [ 23 ].…”

“…This glycolytic reprogramming that occurs inside cardiac MΦ is dependent on hypoxia inducible factor-1 alpha (HIF-1α) [ 23 ]. Both HIF-1α signaling and IL-1β production are independently achieved through the phosphorylation of STAT-1 activation that is promoted by AXL [ 23 ]. It was noted that AXL expression was correlated with the SARS-CoV-2 virus titer in COVID-19 patients, indicating upregulated AXL expression during the infection [ 10 ] and indeed virus replication are further amplified in glucose-rich micro-environment, where virus-induced metabolic alterations occur at the mitochondrial level with reactive oxygen species (ROS) production.…”

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

“…In eukaryotic, approximately 2% kinase domains catalyze the phosphate (PO 4 3− ) transfer of ATP to a particular substrate of hydroxy-tyrosine by posttranslational modification [ 47 ]. Due to the pivotal role of tyrosine phosphorylation via kinase domains, it makes them highly conserved in diverse diseases [ 3 , 4 , 5 , 6 , 9 , 35 , 48 , 49 ]. In EGFR (PDB: 1M14), these domains are made up of a C-lobe (larger) and N-lobe (small).…”