Mitogen‐activated protein kinase signaling in childhood asthma development and environment‐mediated protection

Abstract

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 = .006) with reduced acetylation at histone H4 (p = .012) compared with healthy controls. Farm‐dust stimulation upregulated DUSP1 expression reaching healthy levels and downregulated inflammatory MAPKs on gene and protein levels (PBMCs; p ≤ .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.

Mechanism of Peitu Shengjin Formula Shenlingbaizhu Powder in Treating Bronchial Asthma and Allergic Colitis through Different Diseases with Simultaneous Treatment Based on Network Pharmacology and Molecular Docking

“…In recent years, many studies confirmed that inhibiting PI3K−Akt signaling pathway and MAPK signaling pathway could effectively inhibit allergic airway inflammation, ASMC proliferation and migration, and phenotypic switching, so as to alleviate airway remodeling and airway hyperresponsiveness (AHR) in asthma [ 39 – 42 ]. Additionally, upregulation of dual-specificity phosphatase-1 (DUSP1), a negative regulator in the MAPK signaling pathway, to healthy levels and downregulation of inflammatory MAPKs at the gene and protein levels could reduce the prevalence of childhood asthma [ 43 ]. Proteoglycans enhanced deposition in the airway walls of asthmatics playing a role in airway remodeling, and the difference of deposition in the airway smooth muscle layer of moderate and severe asthmatic patients might affect the functional behavior of airway smooth muscle [ 44 , 45 ].…”

Emerging Roles of Non-Coding RNAs in Childhood Asthma

“…That’s to say, p38 MAPK is vital for allergen induced epithelial production of IL-25 and thymic stromal lymphopoietin (TSLP), further mediating the type-2 allergic response in asthma ( Yu et al, 2010 ; Lin et al, 2015 ; Southworth et al, 2018 ). Previous studies have confirmed that dual-specificity phosphatase1 (DUSP1) also plays vital role in anti-inflammation by deactivating MAPKs through dephosphorylation ( Pulido and Lang, 2019 ; Xin et al, 2021 ; Theodorou et al, 2022 ; Xing and Wong, 2022 ). Besides, Studies have confirmed that JNK is essential for airway inflammation via modulating RAGE/β-catenin signaling ( Huang et al, 2021a ).…”

“…Molecular studies have indicated that Mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase (JNK), are involved in the inflammatory response and development of airway remodeling during childhood asthma ( Lee et al, 2019b ; Jia et al, 2019 ). Concretely, ERK1/2 is involved in airway remodeling ( Defnet et al, 2019 ), while p38 MAPK and JNK are considered as anti-inflammation targets to regulate inflammatory processes via phosphorylation of downstream mediators in childhood asthma ( Kim and Choi, 2010 ; Pulido and Lang, 2019 ; Theodorou et al, 2022 ). However, literatures about the pathogenesis of MAPK pathways in childhood asthma are limited.…”

Editorial to the special issue “Environmental influences on childhood asthma”

“…Baek et al have documented that exposure to phthalates are associated with airway dysfunction in childhood and this effect was partially attributable to increased serum periostin levels (6). Regarding the association between the genes and environment, Theodorou et al (7) have investigated the role of mitogen-activated protein kinase (MAPK) pathway in 232 children who were selected from two cross-sectional cohorts and one birth cohort study. They have isolated peripheral blood mononuclear cells (PBMC) from children with asthma along with healthy controls and stimulated them with farm-dust extracts or lipopolysaccharide.…”