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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Krusche, Johanna^1,2  Twardziok, Monika¹  Rehbach, Katharina¹  Boeck, Andreas¹  Tsang, Miranda S.⁴  Schroeder, Paul C.¹  Kumbrink, Joerg^3,5  Kirchner, Thomas^3,5  Xing, Yuhan⁶  Riedler, Josef^7,8  Dalphin, Jean-Charles⁹  Pekkanen, Juha^10,11  Lauener, Roger^12,13,14,15  Roponen, Marjut¹⁶  Li, Jing¹⁷  Wong, Chun K.¹⁸  Wong, Gary W. K.⁶  Schaub, Bianca^1,2  Ege, Markus^1,2  Depner, Martin¹  Illi, Sabina¹  Loss, Georg¹⁷  Renz, Harald¹⁸  Pfefferle, Petra I.^2,19  Kabesch, Michael²⁰  Genuneit, Jon²¹  Karvonen, Anne M.⁹  Hyvarinen, Anne⁹  Kirjavainen, Pirkka V.⁹  Remes, Sami²²  Braun-Fahrlander, Charlotte^23,24  Roduit, Caroline^11,25  Frei, Remo²⁶  Kaulek, Vincent⁹  Dalphin, Marie-Laure²⁷  Divaret-Chauveau, Amandine²⁷  Doekes, Gert²⁸ 

[1] Univ Hosp, Dr von Hauner Childrens Hosp, Dept Pediat, Pediat Allergol, Munich, Germany

[2] German Ctr Lung Res DZL, Giessen, Germany

[3] Ludwig Maximilians Univ Munchen, Inst Pathol, Fac Med, Munich, Germany

[4] Chinese Univ Hong Kong, Inst Chinese Med, Hong Kong, Hong Kong, Peoples R China

[5] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany

[6] Chinese Univ Hong Kong, Dept Paediat, Fac Med, Prince Wales Hosp, Shatin, Hong Kong, Peoples R China

[7] Childrens Hosp Schwarzach, Schwarzach, Austria

[8] Paracelsus Med Private Univ Salzburg, Teaching Hosp, Salzburg, Austria

[9] Univ Franche Comte, Univ Hosp Besancon, UMR CNRS Chronoenvironment 6249, Besancon, France

[10] Natl Inst Hlth & Welf THL, Dept Hlth Secur, Kuopio, Finland

[11] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[12] Childrens Hosp Eastern Switzerland, St Gallen, Switzerland

[13] Univ Zurich, Zurich, Switzerland

[14] Univ St Gallen, Sch Med, St Gallen, Switzerland

[15] Christine Kuhne Ctr Allergy Care & Educ CK CARE, Davos, Switzerland

[16] Univ Eastern Finland, Dept Environm & Biol Sci, Kuopio, Finland

[17] Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Dept Allergy & Clin Immunol, Guangzhou, Guangdong, Peoples R China

[18] Chinese Univ Hong Kong, Dept Chem Pathol, Shatin, Hong Kong, Peoples R China

[19] Philipps Univ, Fachbereich Med, CBBM, ZTI, Marburg, Germany

[20] KUNO Childrens Univ Hosp Regensburg, Dept Pediat Pneumol & Allergy, Campus St Hedwig, Regensburg, Germany

[21] Ulm Univ, Inst Epidemiol & Med Biometry, Ulm, Germany

[22] Kuopio Univ Hosp, Dept Pediat, Kuopio, Finland

[23] Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[24] Univ Basel, Basel, Switzerland

[25] Univ Zurich, Childrens Hosp, Zurich, Switzerland

[26] Univ Zurich, Swiss Inst Allergy & Asthma Res SIAF, Davos, Switzerland

[27] Univ Besanon, Univ Hosp, Dept Pediat, Besancon, France

[28] Univ Utrecht, IRAS, Div Environm Epidemiol, Utrecht, Netherlands

关键词: A20;    asthma;    childhood;    immune development;    environment;    farming;    inflammatory;    TNFAIP3;    LPS;    protection;   

DOI  :  10.1016/j.jaci.2019.07.029

来源: Elsevier

【 摘 要 】

Background: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-alpha-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling, mediates environmentally induced asthma protection. Objective: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. Methods: 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-kappa B 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. Results: 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-kappa B 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. Conclusion: 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.

【 授权许可】

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