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Publications in Proto Oncogene Protein by NOMIS researchers

Regulation of brain endothelial cell physiology by the TAM receptor tyrosine kinase Mer

NOMIS Researcher(s)

Published in

September 7, 2023

The receptor tyrosine kinase Mer (gene name Mertk) acts in vascular endothelial cells (ECs) to tighten the blood-brain barrier (BBB) subsequent to viral infection, but how this is achieved is poorly understood. We find that Mer controls the expression and activity of a large cohort of BBB regulators, along with endothelial nitric oxide synthase. It also controls, via an Akt-Foxo1 pathway, the expression of multiple angiogenic genes. Correspondingly, EC-specific Mertk gene inactivation resulted in perturbed vascular sprouting and a compromised BBB after induced photothrombotic stroke. Unexpectedly, stroke lesions in the brain were also reduced in the absence of EC Mer, which was linked to reduced plasma expression of fibrinogen, prothrombin, and other effectors of blood coagulation. Together, these results demonstrate that Mer is a central regulator of angiogenesis, BBB integrity, and blood coagulation in the mature vasculature. They may also account for disease severity following infection with the coronavirus SARS-CoV-2. © 2023, Springer Nature Limited.

Research field(s)
Health Sciences

DOI
10.1038/s42003-023-05287-y

The TAM receptor tyrosine kinases Axl and Mer drive the maintenance of highly phagocytic macrophages

NOMIS Researcher(s)

Published in

July 29, 2022

Many apoptotic thymocytes are generated during the course of T cell selection in the thymus, yet the machinery through which these dead cells are recognized and phagocytically cleared is incompletely understood. We found that the TAM receptor tyrosine kinases Axl and Mer, which are co-expressed by a specialized set of phagocytic thymic macrophages, are essential components of this machinery. Mutant mice lacking Axl and Mer exhibited a marked accumulation of apoptotic cells during the time that autoreactive and nonreactive thymocytes normally die. Unexpectedly, these double mutants also displayed a profound deficit in the total number of highly phagocytic macrophages in the thymus, and concomitantly exhibited diminished expression of TIM-4, CD163, and other non-TAM phagocytic engulfment systems in the macrophages that remained. Importantly, these previously unrecognized deficits were not confined to the thymus, as they were also evident in the spleen and bone marrow. They had pleiotropic consequences for the double mutants, also previously unrecognized, which included dysregulation of hemoglobin turnover and iron metabolism leading to anemia.

Research field(s)
Health Sciences, Clinical Medicine, Immunology

DOI
10.3389/fimmu.2022.960401

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

NOMIS Researcher(s)

Published in

August 1, 2020

Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.26508/LSA.202000694

The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity

NOMIS Researcher(s)

Published in

December 1, 2015

The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

Research field(s)
Health Sciences, Clinical Medicine, Immunology

DOI
10.1038/nm.3974

Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells

NOMIS Researcher(s)

Published in

January 1, 2015

Billions of inflammatory leukocytes die and are phagocytically cleared each day. This regular renewal facilitates the normal termination of inflammatory responses, suppressing pro-inflammatory mediators and inducing their anti-inflammatory counterparts. Here we investigate the role of the receptor tyrosine kinase (RTK) Mer and its ligands Protein S and Gas6 in the initial recognition and capture of apoptotic cells (ACs) by macrophages. We demonstrate extremely rapid binding kinetics of both ligands to phosphatidylserine (PtdSer)-displaying ACs, and show that ACs can be co-opsonized with multiple PtdSer opsonins.We further show that macrophage phagocytosis of ACs opsonized with Mer ligands can occur independently of a requirement for αV integrins. Finally, we demonstrate a novel role for Mer in the tethering of ACs to the macrophage surface, and show that Mer-mediated tethering and subsequent AC engulfment can be distinguished by their requirement for Mer kinase activity. Our results identify Mer as a receptor uniquely capable of both tethering ACs to the macrophage surface and driving their subsequent internalization.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1038/cddis.2015.18

Diversification of TAM receptor tyrosine kinase function

NOMIS Researcher(s)

Published in

January 1, 2014

The clearance of apoptotic cells is critical for both tissue homeostasis and the resolution of inflammation. We found that the TAM receptor tyrosine kinases Axl and Mer had distinct roles as phagocytic receptors in these two settings, in which they exhibited divergent expression, regulation and activity. Mer acted as a tolerogenic receptor in resting macrophages and during immunosuppression. In contrast, Axl was an inflammatory response receptor whose expression was induced by proinflammatory stimuli. Axl and Mer differed in their ligand specificities, ligand-receptor complex formation in tissues, and receptor shedding upon activation. These differences notwithstanding, phagocytosis by either protein was strictly dependent on receptor activation triggered by bridging of TAM receptor-ligand complexes to the ‘eat-me’ signal phosphatidylserine on the surface of apoptotic cells.

Research field(s)
Health Sciences, Clinical Medicine, Immunology

DOI
10.1038/ni.2986

Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors

NOMIS Researcher(s)

Published in

August 14, 2013

Upon activation by the ligands Gas6 and Protein S, Tyro3/Axl/Mer (TAM) receptor tyrosine kinases promote phagocytic clearance of apoptotic cells and downregulate immune responses initiated by Toll-like receptors and type I interferons (IFNs). Many enveloped viruses display the phospholipid phosphatidylserine on their membranes, through which they bind Gas6 and Protein S and engage TAM receptors. We find that ligand-coated viruses activate TAM receptors on dendritic cells (DCs), dampen type I IFN signaling, and thereby evade host immunity and promote infection. Upon virus challenge, TAM-deficient DCs display type I IFN responses that are elevated in comparison to wild-type cells. As a consequence, TAM-deficient DCs are relatively resistant to infection by flaviviruses and pseudotyped retroviruses, but infection can be restored with neutralizing type I IFN antibodies. Correspondingly, a TAM kinase inhibitor antagonizes the infection of wild-type DCs. Thus, TAM receptors are engaged by viruses in order to attenuate type I IFN signaling and represent potential therapeutic targets. © 2013 Elsevier Inc.

Research field(s)
Health Sciences, Clinical Medicine, Immunology

DOI
10.1016/j.chom.2013.07.005

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