Allergic bronchial asthma is a chronic disease of the airways that is characterized by symptoms like respiratory distress, chest tightness, wheezing, productive cough, and acute episodes of broncho-obstruction. This symptom-complex arises on the basis of chronic allergic inflammation of the airway wall. Consequently, the airway epithelium is central to the pathogenesis of this disease, because its multiple abilities directly have an impact on the inflammatory response and thus the formation of the disease. In turn, its structure and functions are markedly impaired by the inflammation. Hence, the airway epithelium represents a sealed, self-cleaning barrier, that prohibits penetration of inhaled allergens, pathogens, and other noxious agents into the body. This barrier is covered with mucus that further contains antimicrobial peptides and antibodies that are either produced or specifically transported by the airway epithelium in order to trap these particles and to remove them from the body by a process called mucociliary clearance. Once this first line of defense of the lung is overcome, airway epithelial cells are the first cells to get in contact with pathogens, to be damaged or infected. Therefore, these cells release a plethora of chemokines and cytokines that not only induce an acute inflammatory reaction but also have an impact on the alignment of the following immune reaction. In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Recent studies indicate that the history of allergy- and pathogen-derived insults can leave some kind of memory in these cells that can be described as imprinting or trained immunity. Thus, the airway epithelium is in the center of processes that lead to formation, progression and acute exacerbation of asthma.

IL-17 cytokines are expressed by numerous cells (e.g., gamma delta (γδ) T, innate lymphoid (ILC), Th17, epithelial cells). They contribute to the elimination of bacteria through the induction of cytokines and chemokines which mediate the recruitment of inflammatory cells to the site of infection. However, IL-17-driven inflammation also likely promotes the progression of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), lung cancer, cystic fibrosis, and asthma. In this review, we highlight the role of IL-17 cytokines in chronic lung diseases.

Th2 cells play a central role in the pathogenesis of allergic bronchial asthma, since each of their characteristic cytokines such as IL-4, IL-5, IL-9 and IL-13 contributes to hallmarks of this disease, including airway eosinophilia, increased mucus production, production of allergen-specific IgE and development of airway hyper-responsiveness. Therefore, these cells are predisposed as target cells for therapeutic intervention. Experimental approaches targeted Th2-type effector cytokines, Th2-cell recruitment and Th2-cell development. Another strategy uses the immunomodulatory potential of tolerance-inducing cytokines such as IL-10 or of cytokines such as IL-12, IL-18 and IFN-gamma that are able to induce a counterbalancing Th1 immune response.

Viral infection of the respiratory tract represents the major cause of acute asthma exacerbations. dsRNA is produced as an intermediate during replication of respiratory viruses and triggers immune responses via TLR3. This study aimed at clarifying the mechanisms underlying TLR3 triggered exacerbation of experimental allergic asthma. The TLR3 ligand poly(inosinic-cytidylic) acid was applied intranasally to mice with already established experimental allergic asthma. Airway inflammation, cytokine expression, mucus production, and airway reactivity was assessed in wild-type, IL-17A, or IL-23p19–deficient, and in NK cell–depleted mice. Local application of poly(inosinic-cytidylic) acid exacerbated experimental allergic asthma in mice as characterized by enhanced release of proinflammatory cytokines, aggravated airway inflammation, and increased mucus production together with pronounced airway hyperresponsiveness. This was further associated with augmented production of IL-17 by Th17 cells and NK cells. Whereas experimental exacerbation could be induced in IL-23p19–deficient mice lacking mature, proinflammatory Th17 cells, this was not possible in mice lacking IL-17A or in NK cell–depleted animals. These experiments indicate a central role for IL-17 derived from NK cells but not from Th17 cells in the pathogenesis of virus-triggered exacerbation of experimental asthma.

Background: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL‐37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL‐37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL‐37 controls allergic inflammation.Methods: IL‐37 target cells were identified by single‐cell RNA‐seq of IL‐1R5 and IL‐1R8. Airway tissues were isolated by laser‐capture microdissection and examined by microarray‐based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL‐1β, or IL‐33 together with recombinant human (rh) IL‐37. Wild‐type, IL‐1R1– and IL‐33–deficient mice with EAA were treated with rhIL‐37. IL‐1β, IL‐33, and IL‐37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy.Results: IL‐37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL‐37 led to differential expression of >90 genes induced by IL‐1β and IL‐33. rhIL‐37 reduced production of Th2 cytokines in allergen‐activated MNCs from wild‐type but not from IL‐1R1–deficient mice and inhibited IL‐33–induced Th2 cytokine release. Furthermore, rhIL‐37 attenuated IL‐1β– and IL‐33–induced pro‐inflammatory mediator expression in murine AEC cultures. In contrast to wild‐type mice, hIL‐37 had no effect on EAA in IL‐1R1– or IL‐33–deficient mice. We also observed that expression/production ratios of both IL‐1β and IL‐33 to IL‐37 were dramatically increased in asthma patients compared to healthy controls.Conclusion: IL‐37 downregulates allergic airway inflammation by counterbalancing the disease‐amplifying effects of IL‐1β and IL‐33.