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Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients. [ABSTRACT FROM AUTHOR]

Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2s) are activated within 7 hours after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2s colocalize to sensory neuronal termini expressing the neuropeptide neuromedin U (NMU), which stimulates type 2 (T2) cytokine secretion by ILC2s, with additive effects to alarmins in vitro. Objectives: To investigate the effect of the NMU/NMUR1 (NMU receptor 1) axis on early activation of ILC2s in asthma. Methods: Subjects with mild asthma (n = 8) were enrolled in a diluent-controlled allergen inhalation challenge study. Sputum ILC2 expression of NMUR1 and T2 cytokines was enumerated by flow cytometry, and airway NMU levels were assessed by ELISA. This was compared with samples from subjects with moderate to severe asthma (n = 9). Flow sort–purified and ex vivo–expanded ILC2s were used for functional assays and transcriptomic analyses. Measurements and Main Results: Significant increases in sputum ILC2s expressing NMUR1 were detected 7 hours after allergen versus diluent challenge whereby the majority of NMUR1+ ILC2s expressed IL-5/IL-13. Sputum NMUR1+ ILC2 counts were significantly greater in mild versus moderate to severe asthma, and NMUR1+ ILC2s correlated inversely with the dose of inhaled corticosteroid in the latter group. Coculturing with alarmins upregulated NMUR1 in ILC2s, which was attenuated by dexamethasone. NMU-stimulated T2 cytokine expression by ILC2s, maximal at 6 hours, was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase 1/2 and phosphoinositol 3-kinase but not the IL-33 signaling moiety MyD88 in vitro. Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2s and may be an important early activator of these cells in eosinophilic inflammatory responses in asthma. [ABSTRACT FROM AUTHOR]

This article examines the protein expression of ACE2 and TMPRSS2 receptors in the airways of individuals with allergic asthma and allergic rhinitis after allergen challenge. The study found that allergen challenge led to a significant reduction in the number of cells expressing ACE2 and TMPRSS2 receptors in the bronchial tissue of individuals with allergic asthma. However, no significant changes were observed in the nasal tissue of individuals with allergic rhinitis. The authors hypothesized that elevated levels of IL-13, a type 2 cytokine, after allergen challenge may regulate ACE2 protein expression in the airways. The study suggests that while IL-13 may dampen ACE2 and TMPRSS2 receptor expression, other factors contribute to the rate of SARS-CoV-2 infectivity and hospitalization in individuals with asthma. [Extracted from the article]

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)‐33, and IL‐25 are epithelial cell‐derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen‐induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti‐TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2‐high and with T2‐low asthma. Clinical trials blocking IL‐33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL‐33/ST2 axis in T2‐high versus T2‐low asthma is unclear. To date, there is no evidence that IL‐25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL‐25, IL‐33, and TSLP, they appear to have distinct roles in the immunopathology of asthma. [ABSTRACT FROM AUTHOR]