Therapeutic efficacy of IL-17A neutralization with corticosteroid treatment in a model of antigen-driven mixed-granulocytic asthma

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 319; no. 4; pp. L693 - L709
• Main Authors: Menson, Katherine E, Mank, Madeleine M, Reed, Leah F, Walton, Camille J, Van Der Vliet, Katherine E, Ather, Jennifer L, Chapman, David G, Smith, Bradford J, Rincon, Mercedes, Poynter, Matthew E
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.10.2020
• Subjects: Adrenal Cortex Hormones - pharmacology; Allergens - drug effects; Allergens - immunology; Allergic diseases; Alveoli; Amyloid; Animal models; Animals; Antigens; Asthma; Asthma - drug therapy; Asthma - pathology; Biomarkers; Body weight; Body weight loss; Bronchus; Corticosteroids; Cytokines; Cytology; Dexamethasone; Eosinophils; Eosinophils - drug effects; Eosinophils - pathology; Freund's adjuvant; Helper cells; House dust; Inflammation; Inflammation - drug therapy; Inflammation - pathology; Interleukin 6; Interleukin 6 receptors; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lung - drug effects; Lung - pathology; Lymphocytes; Lymphocytes T; Methacholine; Mice, Inbred C57BL; Neutralization; Neutrophils - drug effects; Neutrophils - immunology; Respiratory Hypersensitivity - pathology; Respiratory tract diseases; Rodents; Steroids; Th17 Cells - drug effects; Th17 Cells - immunology; Weight loss; interleukin-17; asthma; corticosteroids; mice; neutrophils
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/AJPLUNG.00204.2020

Many mouse models of allergic asthma exhibit eosinophil-predominant cellularity rather than the mixed-granulocytic cytology in steroid-unresponsive severe disease. Therefore, we sought to implement a novel mouse model of antigen-driven, mixed-granulocytic, severe allergic asthma to determine biomarkers of the disease process and potential therapeutic targets. C57BL/6J wild-type, interleukin-6 knockout (IL-6-/-), and IL-6 receptor knockout (IL-6R-/-), mice were injected with an emulsion of complete Freund's adjuvant and house dust mite antigen (CFA/HDM) on . Dexamethasone, a lymphocyte-depleting biological, or anti-IL-17A was administered during the intranasal HDM challenge on . On , the CFA/HDM model elicited mixed bronchoalveolar lavage (BAL) cellularity (typically 80% neutrophils and 10% eosinophils), airway hyperresponsiveness (AHR) to methacholine, diffusion impairment, lung damage, body weight loss, corticosteroid resistance, and elevated levels of serum amyloid A (SAA), pro-inflammatory cytokines, and T helper type 1/ T helper type 17 (Th1/Th17) cytokines compared with eosinophilic models of HDM-driven allergic airway disease. BAL cells in IL-6- or IL-6R-deficient mice were predominantly eosinophilic and associated with elevated T helper type 2 (Th2) and reduced Th1/Th17 cytokine production, along with an absence of SAA. Nevertheless, AHR remained in IL-6-deficient mice even when dexamethasone was administered. However, combined administration of anti-IL-17A and systemic corticosteroid significantly attenuated both overall and neutrophilic airway inflammation and also reduced AHR and body weight loss. Inhibition of IL-17A combined with systemic corticosteroid treatment during antigen-driven exacerbations may provide a novel therapeutic approach to prevent the pathological pulmonary and constitutional changes that greatly impact patients with the mixed-granulocytic endotype of severe asthma.