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Ligand-dependent kinase activity of MERTK drives efferocytosis in human iPSC-derived macrophages.
Wanke, Florian; Gutbier, Simon; Rümmelin, Anna; Steinberg, Malte; Hughes, Lindsey D; Koenen, Mascha; Komuczki, Juliana; Regan-Komito, Daniel; Wagage, Sagie; Hesselmann, Julia; Thoma, Ralf; Brugger, Doris; Christopeit, Tony; Wang, Hayian; Point, Floriane; Hallet, Remy; Ghosh, Sourav; Rothlin, Carla V; Patsch, Christoph; Geering, Barbara.
Affiliation
  • Wanke F; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland. florian.wanke@roche.com.
  • Gutbier S; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
  • Rümmelin A; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
  • Steinberg M; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
  • Hughes LD; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
  • Koenen M; Yale School of Medicine, Department for Immunobiology, Yale University, New Haven, Connecticut, USA.
  • Komuczki J; Yale School of Medicine, Department for Immunobiology, Yale University, New Haven, Connecticut, USA.
  • Regan-Komito D; Laboratory of Molecular Metabolism, Rockefeller University, New York, New York, USA.
  • Wagage S; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
  • Hesselmann J; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
  • Thoma R; Yale School of Medicine, Department for Immunobiology, Yale University, New Haven, Connecticut, USA.
  • Brugger D; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
  • Christopeit T; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
  • Wang H; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
  • Point F; Roche Pharma Research and Early Development, Roche Innovation Center München, Penzberg, Germany.
  • Hallet R; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
  • Ghosh S; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
  • Rothlin CV; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
  • Patsch C; Yale School of Medicine, Department for Neurology, Yale University, New Haven, Connecticut, USA.
  • Geering B; Yale School of Medicine, Department for Pharmacology, Yale University, New Haven, Connecticut, USA.
Cell Death Dis ; 12(6): 538, 2021 05 25.
Article in En | MEDLINE | ID: mdl-34035216
ABSTRACT
Removal of apoptotic cells by phagocytes (also called efferocytosis) is a crucial process for tissue homeostasis. Professional phagocytes express a plethora of surface receptors enabling them to sense and engulf apoptotic cells, thus avoiding persistence of dead cells and cellular debris and their consequent effects. Dysregulation of efferocytosis is thought to lead to secondary necrosis and associated inflammation and immune activation. Efferocytosis in primarily murine macrophages and dendritic cells has been shown to require TAM RTKs, with MERTK and AXL being critical for clearance of apoptotic cells. The functional role of human orthologs, especially the exact contribution of each individual receptor is less well studied. Here we show that human macrophages differentiated in vitro from iPSC-derived precursor cells express both AXL and MERTK and engulf apoptotic cells. TAM RTK agonism by the natural ligand growth-arrest specific 6 (GAS6) significantly enhanced such efferocytosis. Using a newly-developed mouse model of kinase-dead MERTK, we demonstrate that MERTK kinase activity is essential for efferocytosis in peritoneal macrophages in vivo. Moreover, human iPSC-derived macrophages treated in vitro with blocking antibodies or small molecule inhibitors recapitulated this observation. Hence, our results highlight a conserved MERTK function between mice and humans, and the critical role of its kinase activity in homeostatic efferocytosis.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phagocytosis / C-Mer Tyrosine Kinase / Macrophages Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cell Death Dis Year: 2021 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phagocytosis / C-Mer Tyrosine Kinase / Macrophages Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cell Death Dis Year: 2021 Document type: Article Affiliation country: