title: TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology.
abstract: Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis.
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez-Lloret
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Yanda
authors.initials: Y
authors.lastname: Li
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Entwistle
authors.affiliation: Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Hania
authors.initials: H
authors.lastname: Khoury
authors.affiliation: Immune Cell Signaling Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Stamatia
authors.initials: S
authors.lastname: Papoutsopoulou
authors.affiliation: Experimental Histopathology, Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Radma
authors.initials: R
authors.lastname: Mahmood
authors.affiliation: Department of Infection and Immunity, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Nuha R
authors.initials: NR
authors.lastname: Mansour
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Stanley
authors.initials: S
authors.lastname: Ching-Cheng Huang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
authors.affiliation: Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Luiz
authors.initials: L
authors.lastname: Pedro S de Carvalho
authors.affiliation: Immune Cell Signaling Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Mark S
authors.identifier: 0000-0003-1737-1281
authors.initials: MS
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005355:Fibrosis; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008066:Lipolysis / Q000235:genetics / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse