title: The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages.
abstract: Tumor-associated macrophages (TAMs) are a major supportive component within neoplasms. Mechanisms of macrophage (MΦ) attraction and differentiation to a tumor-promoting phenotype, which is characterized by pronounced interleukin (IL)-10 production, are under investigation. We report that supernatants of dying cancer cells induced substantial IL-10 release from primary human MΦs, dependent on signaling through tyrosine kinase receptor A (TRKA or neurotrophic tyrosine kinase receptor type 1 (NTRK1)). Mechanistically, sphingosine-1-phosphate (S1P) release from apoptotic cancer cells triggered src-dependent shuttling of cytosolic TRKA to the plasma membrane via S1P receptor signaling. Plasma membrane-associated TRKA, which was activated by constitutively autocrine secreted nerve growth factor, used phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase (MAPK) signaling to induce IL-10. Interestingly, TRKA-dependent signaling was required for cytokine production by TAMs isolated from primary murine breast cancer tissue. Besides IL-10, this pathway initiated secretion of IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), indicating relevance in cancer-associated inflammation. Our findings highlight a fine-tuned regulatory system including S1P-dependent TRKA trafficking for executing TAM-like cell function in vitro as well as in vivo.
authors.affiliation: Institute of Biochemistry I/ZAFES, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ley
authors.forename: A
authors.initials: A
authors.lastname: Weigert
authors.forename: B
authors.initials: B
authors.lastname: Weichand
authors.forename: N
authors.initials: N
authors.lastname: Henke
authors.forename: B
authors.initials: B
authors.lastname: Mille-Baker
authors.forename: R A J
authors.initials: RA
authors.lastname: Janssen
authors.forename: B
authors.initials: B
authors.lastname: Brüne
mesh_terms: D000818:Animals; D016753:Interleukin-10 / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D016753:Interleukin-10; C060506:sphingosine 1-phosphate; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D013110:Sphingosine