Abstract
BackgroundThe 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.ObjectiveTPL-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.MethodsA 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.ResultsTPL-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.ConclusionsTPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice.
Highlights
The molecular and cellular pathways driving the pathogenesis of severe asthma are poorly defined
We found that T-cell receptor (TCR) activation of ERK1/2 in purified CD41 T cells was completely independent of Tumor progression locus 2 (TPL-2).17 These results prompted us to formally test whether Tcell–intrinsic TPL-2 was required for type 2 immunity in vivo using a clinically relevant allergen, house dust mite (HDM),[20] in various models of allergic airway inflammation
These results suggested that the absence of TPL-2 in dendritic cell (DC) was responsible for increased Ccl[24] in the bronchoalveolar lavage (BAL) of HDM-challenged Map3k82/2 mice, which correlated with severe airway allergy (Fig 4, B-D, and Fig 6, D)
Summary
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 Map3k82/2 mice was conducted. Differential cell counts were performed on the bronchoalveolar lavage fluid, followed by histological analysis of lung sections. ELISA was used to assess the production of IgE, type 2 cytokines, and Ccl[24]. 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 Map3k82/2 mice were not due to a cell-intrinsic role for TPL-2 in T cells, B cells, or
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