TY - JOUR
T1 - Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells
AU - Kannan, Yashaswini
AU - Li, Yanda
AU - Coomes, Stephanie M
AU - Okoye, Isobel S
AU - Pelly, Victoria
AU - Sriskantharajah, Srividya
AU - Gückel, Eva
AU - Webb, Lauren
AU - Czieso, Stephanie
AU - Nikolov, Nikolay
AU - MacDonald, Andrew
AU - Ley, Steven C
AU - Wilson, Mark S
N1 - Copyright © 2016 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.
PY - 2017/2/2
Y1 - 2017/2/2
N2 - BACKGROUND: 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.OBJECTIVE: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: TPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice.
AB - BACKGROUND: 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.OBJECTIVE: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: TPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice.
U2 - 10.1016/j.jaci.2016.05.031
DO - 10.1016/j.jaci.2016.05.031
M3 - Article
C2 - 27484038
SN - 0091-6749
VL - 139
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -
