Weixi Zhang

Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlighting their vital role in triggering and escalating the progression of asthma. Myeloid differentiation primary response protein 88 (MyD88) controls innate and adaptive immune responses by orchestrating inflammatory signals. This work focused on investigating the influence of MyD88 in governing ILC2s-driven allergic airway disease alongside its underlying molecular mechanisms. We evaluated the effects of MyD88 in IL-33-induced or allergen-induced airway hyperreactivity (AHR) and airway inflammation. The role and mechanism of MyD88 in regulating ILC2s function were examined in vivo and in vitro by using transcriptome sequencing analysis, flow cytometry, clinical samples, ILC2-specific MyD88 knockout mice, and anti-Thy1.2 antibody against ILC2s in mice. The results showed heightened MyD88 expression in ILC2s sourced from allergic asthmatic patients and asthmatic mice. MyD88 knockout in ILC2s was able to mitigate IL-33-induced airway inflammation, while the MyD88 inhibitor LM8 proves efficacious in attenuating allergen-induced airway inflammation and AHR. After elimination of ILC2s via anti-Thy1.2 antibody, the pharmacological activity of LM8 diminished. Mechanistic studies revealed that MyD88 mediates the activation and proliferation of ILC2s through facilitation of P38-GATA3 complex formation. The research highlights MyD88 as a critical regulator of ILC2s activation, suggesting its potential utility as a therapeutic target for interventions in allergic asthma.

Asthma is a prevalent chronic airway disorder characterized by airway hyperresponsiveness (AHR), persistent airway inflammation, and airway remodeling. Emerging evidence implicates ubiquitination‐a critical post‐translational modification‐in asthma pathogenesis. The study identifies ovarian tumor deubiquitinase 6A (OTUD6A), a deubiquitinase with established oncogenic roles, as a novel regulator of airway inflammation and remodeling. The study finds a significantly upregulation of OTUD6A in asthma patients and murine lungs, with predominant localization in airway epithelial cells. Genetic ablation of Otud6a prevents house dust mite (HDM)‐induced AHR, airway inflammation, mucin hypersecretion in both chronic and acute asthma models, as well as airway remodeling in chronic asthma model. Mechanistically, multi‐omics analysis identifies the secreted cytokine human (h)Resistin/mouse resistin‐like molecule α (mRELMα) as a substrate of OTUD6A. OTUD6A deubiquitinates and stabilizes hResistin by specifically removing its K48‐linked polyubiquitin chains at lysines K2 and K19 via the catalytic residue C152, thereby blocking its proteasomal degradation and promoting its secretion. The consequent accumulation of hResistin potentiates epithelial alarms production and facilitates epithelial‐mesenchymal transition, driving airway inflammation and airway remodeling. Furthermore, adeno‐associated virus 6‐mediated OTUD6A silencing in murine lungs markedly ameliorates asthma phenotypes. These findings establish a pathogenic OTUD6A‐hResistin/mRELMα axis and nominating OTUD6A as a promising therapeutic target for asthma intervention.

Introduction: Asthma has an annual increasing morbidity rate and imposes a heavy social burden on public healthcare systems. The aim of this study was to use machine learning to identify asthma-specific genes for the prediction and diagnosis of asthma.Methods: Differentially expressed genes (DEGs) related to asthma were identified by examining public sequencing data from the Gene Expression Omnibus, coupled with the support vector machine recursive feature elimination and least absolute shrinkage and selection operator regression model. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis and correlation analyses between gene and immune cell levels were performed. An ovalbumin-induced asthma mouse model was established, and eukaryotic reference transcriptome high-throughput sequencing was performed to identify genes expressed in mouse lung tissues.Results: Thirteen specific asthma genes were obtained from our dataset analysis (LOC100132287, CEACAM5, PRR4, CPA3, POSTN, LYPD2, TCN1, SCGB3A1, NOS2, CLCA1, TPSAB1, CST1, and C7orf26). The GO analysis demonstrated that DEGs linked to asthma were primarily related to positive regulation of guanylate cyclase activity, gpi anchor binding, peptidase activity and arginine binding. The renin-angiotensin system, arginine biosynthesis and arginine and proline metabolism were the key KEGG pathways of DEGs. Additionally, the genes CEACAM5, PRR4, CPA3, POSTN, CLCA1, and CST1 expression levels were positively associated with plasma cells and resting mast cells. The mouse model revealed elevated nos2 and clca1 expression in the asthmatic mouse group compared with that in normal mice, which was consistent with the findings in asthmatic patients.Discussion: This study identified new marker genes for the prediction and diagnosis of asthma, which can be further validated and applied clinically

Introduction: Group 2 innate lymphoid cells (ILC2s) play a crucial role in house dust mite (HDM)-induced allergic inflammation, and allergen immunotherapy (AIT) holds promise for treating the disease by reducing the frequency of ILC2s. Despite significant progress in AIT for allergic diseases, there remains a need to improve the control of allergic symptoms.Methods: We investigated the synergistic effect of the Notch signaling pathway and subcutaneous immunotherapy (SCIT) in treating allergic airway inflammation in mice and their impact on the ratio of ILC2s in lung tissues. This was achieved by establishing the HDM-induced airway allergic disorders (HAAD) model and SCIT model. Additionally, we conducted in vitro investigations into the effect of the Notch signaling pathway on the secretory function of activated ILC2s using fluorescence-activated cell sorting. Furthermore, we explored the coactivation of the Notch signaling pathway with SCIT in vitro by sorting ILC2s from the lung tissues of mice after SCIT modeling.Results: Previously, our group demonstrated that Notch signaling pathway inhibitors can reduce allergic airway inflammation in mice. Notch signaling induces lineage plasticity of mature ILC2s. In this study, we showed that AIT alleviates allergic airway inflammation and suppresses the frequency of ILC2s induced by HDM. Interestingly, AIT combined with a γ-secretase inhibitor (GSI), an inhibitor of the Notch signaling pathway, significantly inhibited the frequency of ILC2s, reduced airway inflammation, and suppressed Th2-type responses in a mouse model. Furthermore, lung ILC2s from HDM-challenged mice with or without AIT were treated with GSI in vitro, and we found that GSI dramatically reduced the secretion of type 2 inflammatory factors in ILC2s.Discussion: These findings suggest that Notch signaling pathway inhibitors can be used as adjuvant therapy for AIT and may hold potential treatment value in the cooperative control of allergic airway inflammation during early AIT.