BACKGROUND: While childhood asthma prevalence is rising in westernized countries, farm children are protected. The mitogen-activated protein kinase (MAPK) pathway with its negative regulator dual-specificity phosphatase-1 (DUSP1) is presumably associated with asthma development. OBJECTIVES: We aimed to investigate the role of MAPK signaling in childhood asthma and its environment-mediated protection, including a representative selection of 232 out of 1062 children from two cross-sectional cohorts and one birth cohort study. METHODS: Peripheral blood mononuclear cells (PBMC) from asthmatic and healthy children were cultured upon stimulation with farm-dust extracts or lipopolysaccharide. In subgroups, gene-expression was analyzed by qPCR (PBMCs, cord blood) and NanoString-technology (dendritic cells). Protein expression of phosphorylated MAPKs was measured by mass cytometry. Histone acetylation was investigated by Chromatin Immunoprecipitation. RESULTS: Asthmatic children expressed significantly less DUSP1 (p=0.006) with reduced acetylation at histone H4 (p=0.012) compared to healthy controls. Farm-dust stimulation upregulated DUSP1 expression reaching healthy levels and downregulated inflammatory MAPKs on gene and protein levels (PBMCs; p≤0.01). Single-cell protein analysis revealed downregulated pMAPKs upon farm-dust stimulation in B-cells, NK-cells, monocytes, and T-cell subpopulations. CONCLUSION: Lower DUSP1 baseline levels in asthmatic children and anti-inflammatory regulation of MAPK in several immune cell types by farm-dust stimulation indicate a regulatory function for DUSP1 for future therapy contributing to anti-inflammatory characteristics of farming environments.
- Theodorou, J.
- Nowak, E.
- Böck, A.
- Salvermoser, M.
- Beerweiler, C.
- Zeber, K.
- Kulig, P.
- Tsang, M. S.
- Wong, C. K.
- Wong, G. W. K.
- Roponen, M.
- Kumbrink, J.
- Alhamdan, F.
- Michel, F.
- Garn, H.
- Tosevski, V.
- Schaub, B.
Keywords
- Mapk
- allergy
- asthma
- childhood
- farming
- immunology
- protection
