title: Tpl2 kinase regulates FcγR signaling and immune thrombocytopenia in mice.
abstract: The MAPK3 Tpl2 controls innate and adaptive immunity by regulating TLR, TNF-α, and GPCR signaling in a variety of cell types. Its ablation gives rise to an anti-inflammatory phenotype characterized by resistance to LPS-induced endotoxin shock, DSS-induced colitis, and TNF-α-induced IBD. Here, we address the role of Tpl2 in autoimmunity. Our data show that the ablation and the pharmacological inhibition of Tpl2 protect mice from antiplatelet antibody-induced thrombocytopenia, a model of ITP. Thrombocytopenia in this model and in ITP is caused by phagocytosis of platelets opsonized with antiplatelet antibodies and depends on FcγR activation in splenic and hepatic myeloid cells. Further studies explained how Tpl2 inhibition protects from antibody-induced thrombocytopenia, by showing that Tpl2 is activated by FcγR signals in macrophages and that its activation by these signals is required for ERK activation, cytoplasmic Ca(2+) influx, the induction of cytokine and coreceptor gene expression, and phagocytosis.
authors.affiliation: 2.Div. of Allergy, Clinical Immunology and Rheumatology, New York Medical College, 40 Sunshine Cottage Rd., Valhalla, NY 10595, USA. Ioannis_Tassiulas@nymc.edu.
authors.forename: Irene
authors.initials: I
authors.lastname: Kyrmizi
authors.forename: Marianna
authors.initials: M
authors.lastname: Ioannou
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
authors.forename: Ioannis
authors.initials: I
authors.lastname: Tassiulas
mesh_terms: D000818:Animals; D000906:Antibodies; D002118:Calcium / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000906:Antibodies; D003432:Cross-Linking Reagents; D016207:Cytokines; C485701:Fcgr1 protein, mouse; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D002118:Calcium
keywords: MAPK; immune complex; macrophages
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