title: Btk is a positive regulator in the TREM-1/DAP12 signaling pathway.
abstract: The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca²⁺ mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-α and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-α production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes.
authors.affiliation: German Cancer Research Center (DKFZ), Innate Immunity, Heidelberg, Germany.
authors.forename: Tereza
authors.initials: T
authors.lastname: Ormsby
authors.forename: Eva
authors.initials: E
authors.lastname: Schlecker
authors.forename: Janina
authors.initials: J
authors.lastname: Ferdin
authors.forename: Anja Sibylle
authors.initials: AS
authors.lastname: Tessarz
authors.forename: Pavla
authors.initials: P
authors.lastname: Angelisová
authors.forename: Afitap Derya
authors.initials: AD
authors.lastname: Köprülü
authors.forename: Michael
authors.initials: M
authors.lastname: Borte
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.forename: Ilka
authors.initials: I
authors.lastname: Schulze
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.forename: Václav
authors.initials: V
authors.lastname: Horejsí
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000378:metabolism; D000818:Animals; D002469:Cell Separation; D005434:Flow Cytometry; D040181:Genetic Diseases, X-Linked / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C110546:TYROBP protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse