TNF-α–induced protein 3 is a key player in childhood asthma development and environment-mediated protection

Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α–induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediat...

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Published in:	Journal of allergy and clinical immunology Vol. 144; no. 6; pp. 1684 - 1696.e12
Main Authors:	Krusche, Johanna, Twardziok, Monika, Rehbach, Katharina, Böck, Andreas, Tsang, Miranda S., Schröder, Paul C., Kumbrink, Jörg, Kirchner, Thomas, Xing, Yuhan, Riedler, Josef, Dalphin, Jean-Charles, Pekkanen, Juha, Lauener, Roger, Roponen, Marjut, Li, Jing, Wong, Chun K., Wong, Gary W.K., Schaub, Bianca, Ege, Markus, Depner, Martin, Illi, Sabina, Loss, Georg J., Renz, Harald, Pfefferle, Petra I., Kabesch, Michael, Genuneit, Jon, Karvonen, Anne M., Hyvärinen, Anne, Kirjavainen, Pirkka V., Remes, Sami, Braun-Fahrländer, Charlotte, Roduit, Caroline, Frei, Remo, Kaulek, Vincent, Dalphin, Marie-Laure, Divaret-Chauveau, Amandine, Doekes, Gert
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-12-2019 Elsevier Limited
Subjects:	A20 A20 protein Age Allergies Asthma Birth Blood cells childhood Children Cord blood Dendritic cells Dust environment Environmental effects Environmental factors Ethics Exposure farming Farms Gene expression Genotype & phenotype Hypotheses immune development Immunological tolerance Immunomodulation Inflammation inflammatory Laboratories Leukocytes (mononuclear) Lipopolysaccharides LPS Lymphocytes B Neonates NF-κB protein Pregnancy protection Rural areas Rural environments TLR4 protein TNFAIP3 Toll-like receptors Tumor necrosis factor-α Urban agriculture Austria China Finland Hong Kong China France Switzerland Germany immune development inflammatory TNFAIP3 protection CLARA/CLAUS LPS MALT1 NF-κB OTU IRAK1 farming PASTURE/EFRAIM CTLA4 MANOVA PAULINA/PAULCHEN AA childhood asthma CBMC PVDF CT environment TNIP2 LAL TRAF6 TAX1BP1 ROX HC PDCD1 TLR4 MYD88 A20 DC
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Summary:	Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α–induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediates environmentally induced asthma protection. We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from “asthma-protective” farms or LPS. NF-κB signaling–related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P < .05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-κB signaling–associated gene expression toward an anti-inflammatory state (P < .001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment. [Display omitted]
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0091-6749 1097-6825
DOI:	10.1016/j.jaci.2019.07.029