title: Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells.
abstract: The molecular and cellular pathways driving the pathogenesis of severe asthma are poorly defined. Tumor progression locus 2 (TPL-2) (COT, MAP3K8) kinase activates the MEK1/2-extracellular-signal regulated kinase 1/2 MAP kinase signaling pathway following Toll-like receptor, TNFR1, and IL-1R stimulation.
  
  
  
  TPL-2 has been widely described as a critical regulator of inflammation, and we sought to investigate the role of TPL-2 in house dust mite (HDM)-mediated allergic airway inflammation.
  
  
  
  A comparative analysis of wild-type and Map3k8-/-mice was conducted. Mixed bone marrow chimeras, conditional knockout mice, and adoptive transfer models were also used. Differential cell counts were performed on the bronchoalveolar lavage fluid, followed by histological analysis of lung sections. Flow cytometry and quantitative PCR was used to measure type 2 cytokines. ELISA was used to assess the production of IgE, type 2 cytokines, and Ccl24. RNA sequencing was used to characterize dendritic cell (DC) transcripts.
  
  
  
  TPL-2 deficiency led to exacerbated HDM-induced airway allergy, with increased airway and tissue eosinophilia, lung inflammation, and IL-4, IL-5, IL-13, and IgE production. Increased airway allergic responses in Map3k8-/-mice were not due to a cell-intrinsic role for TPL-2 in T cells, B cells, or LysM+cells but due to a regulatory role for TPL-2 in DCs. TPL-2 inhibited Ccl24 expression in lung DCs, and blockade of Ccl24 prevented the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8-/-DCs.
  
  
  
  TPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice.
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Yanda
authors.initials: Y
authors.lastname: Li
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Coomes
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Isobel S
authors.initials: IS
authors.lastname: Okoye
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Pelly
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Srividya
authors.initials: S
authors.lastname: Sriskantharajah
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Eva
authors.initials: E
authors.lastname: Gückel
authors.affiliation: Faculty of Life Sciences, Manchester Collaborative Centre for Inflammation Research, the University of Manchester, Manchester, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Webb
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czieso
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Nikolov
authors.affiliation: Faculty of Life Sciences, Manchester Collaborative Centre for Inflammation Research, the University of Manchester, Manchester, United Kingdom.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom. Electronic address: Steve.Ley@crick.ac.uk.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, the Ridgeway, London, United Kingdom. Electronic address: Mark.Wilson@crick.ac.uk.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D054423:Chemokine CCL24 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology*; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D039981:Pyroglyphidae / Q000276:immunology; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology
chemical_list: D039741:Antigens, Dermatophagoides; D054423:Chemokine CCL24; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D007073:Immunoglobulin E; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse
keywords: Ccl24; Map3k8(−/−); TPL-2; allergy; dendritic cells; eotaxin-2; house dust mite; severe asthma