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Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1⁻/⁻ mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.

Asthma is characterized by airway hyperreactivity and inflammation. In the lungs, parasympathetic and sensory nerves control airway tone and induce bronchoconstriction. Dysregulation of these nerves results in airway hyperreactivity. Humans with eosinophilic asthma have significantly increased sensory nerve density in airway epithelium, suggesting that type 2 cytokines and inflammatory cells promote nerve growth. Similarly, mice with congenital airway eosinophilia also have airway hyperreactivity and increased airway sensory nerve density. Here, we tested whether this occurs during development. We show that transgenic mice that overexpress IL-5, a cytokine required for eosinophil hematopoiesis, give birth to wild-type offspring that have significantly increased airway epithelial nerve density and airway hyperreactivity that persists into adulthood. These effects are caused by exposure to maternal IL-5 and resulting fetal eosinophilia. Allergen exposure of these adult wild-type offspring results in severe airway hyperreactivity, leading to fatal reflex bronchoconstriction. Our results demonstrate that fetal exposure to IL-5 is a developmental origin of airway hyperreactivity, mediated by hyperinnervation of airway epithelium.

The mechanisms underlying the association between obesity and the development of asthma remain incompletely understood. Dale T. Umetsu and his colleagues report that the number of IL-17A + type 3 innate lymphoid cells (ILCs) is increased in the lungs of mice fed a high-fat diet. Activation of the NLRP3 inflammasome in lung macrophages promotes IL-1β production and ILC development, and blockade of IL-1 signaling inhibits airway hyperreactivity in obese mice. As these ILCs are also found in the lungs of individuals with asthma, these results suggest that this pathway may be targeted in asthma. Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1 −/− mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a −/− or Nlrp3 −/− mice. AHR was also associated with the expansion of CCR6 + type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2 −/− ; Il2rg −/− mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.

Vitamins play a crucial role in the proper functioning of organisms. Disturbances of their levels, seen as deficiency or excess, enhance the development of various diseases, including those of the cardiovascular, immune, or respiratory systems. The present paper aims to summarize the role of vitamins in one of the most common diseases of the respiratory system, asthma. This narrative review describes the influence of vitamins on asthma and its main symptoms such as bronchial hyperreactivity, airway inflammation, oxidative stress, and airway remodeling, as well as the correlation between vitamin intake and levels and the risk of asthma in both pre- and postnatal life.

Group 2 Innate lymphoid cells (ILC2) contribute significantly to allergic inflammation. However, the role of microbiota on ILC2s remains to be unraveled. Here we show that short chain fatty acids (SCFAs), such as butyrate, derived from fermentation of dietary fibers by the gut microbiota inhibit pulmonary ILC2 functions and subsequent development of airway hyperreactivity (AHR). We further show that SCFAs modulate GATA3, oxidative phosphorylation, and glycolytic metabolic pathways in pulmonary ILC2s. The observed phenotype is associated with increased IL-17a secretion by lung ILC2s and linked to enhanced neutrophil recruitment to the airways. Finally, we show that butyrate-producing gut bacteria in germ-free mice effectively suppress ILC2-driven AHR. Collectively, our results demonstrate a previously unrecognized role for microbial-derived SCFAs on pulmonary ILC2s in the context of AHR. The data suggest strategies aimed at modulating metabolomics and microbiota in the gut, not only to treat, but to prevent lung inflammation and asthma.

Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing T-helper cell type 2 (Th2) skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109-deficient mice (CD109−/−) were sensitized with house dust mite or ovalbumin and compared with wild-type mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared with wild-type mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109−/− mice had a poor ability to induce cytokine production in ex vivo DC–T cell cocultures with high expression of RUNX3 (runt-related transcription factor 3), resulting in suppression of Th2 differentiation. Adoptive transfer of bone marrow–derived CD109−/− DCs loaded with house dust mite failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

Abstract Asthma is a heterogeneous inflammatory airway disease that develops in response to a combination of genetic predisposition and environmental exposures. Patients with asthma are grouped into phenotypes with shared clinical features and biomarker profiles to help tailor specific therapies. However, factors driving development of specific phenotypes are poorly understood. Prenatal exposure to maternal asthma is a unique risk factor for childhood asthma. Here we tested whether maternal asthma skews asthma phenotypes in offspring. We compared airway hyperreactivity and inflammatory and neurotrophin lung signatures before and after allergen challenge in offspring born to mice exposed to house dust mite (HDM) or vehicle during pregnancy. Maternal HDM exposure potentiated offspring responses to HDM allergen, significantly increasing both airway hyperreactivity and airway eosinophilia compared with control mice. Maternal HDM exposure broadly skewed the offspring cytokine response from a classic allergen-induced T-helper cell type 2 (Th2)-predominant signature in HDM-treated offspring of vehicle-exposed mothers, toward a mixed Th17/Th1 phenotype in HDM-treated offspring of HDM-exposed mothers. Morphologic analysis determined that maternal HDM exposure also increased airway epithelial sensory nerve density and induced distinct neurotrophin signatures to support airway hyperinnervation. Our results demonstrate that maternal allergen exposure alters fetal lung development and promotes a unique inflammatory phenotype at baseline and in response to allergen that persists into adulthood.

Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese. To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity. We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time. Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = -0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery. Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.

[This corrects the article DOI: 10.3389/fimmu.2022.849155.].[This corrects the article DOI: 10.3389/fimmu.2022.849155.].

Background P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. Methods Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. Results Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. Conclusions Filapixant proved to be efficacious, safe, and—apart from the occurrence of taste disturbances, especially at higher dosages—well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168