Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma.

Tabata M Dos Santos,Beatriz M Saraiva-Romanholo,Edna A Leick,Carla M Prado,Renato F Righetti,Maria I C Alonso-Vale,Flávia C R De Souza,Silvia Fukuzaki,Leandro Do N Camargo,Milton A Martins,Maysa M Cruz,Iolanda F L C Tibério,Luciana R C R B Aristoteles

doi:10.3389/fphys.2018.01183

Abstract

Background: Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease.Objective: To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation.Methods: Sixty-four BALBc mice, were divided into eight groups (n = 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 μg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28).Results: Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4+, CD8+, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-β, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-β, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05).Conclusion: Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.

Highlights

Asthma is a chronic airway disease characterized by bronchial hyper-responsiveness, lung inflammation, airway remodeling, and airway obstruction (Meyer et al, 2014; Rampadarath and Donovan, 2018)
Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4+, CD8+, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, tumor necrosis factor-α (TNF-α), TGF-β, nuclear factor (NF)-κB, dendritic cells, inducible nitric oxide synthase (iNOS), metalloproteinase 9 (MMP-9), metalloproteinase 12 (MMP-12), TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05)
Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGFβ, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05)

Summary

Introduction

Asthma is a chronic airway disease characterized by bronchial hyper-responsiveness, lung inflammation, airway remodeling, and airway obstruction (Meyer et al, 2014; Rampadarath and Donovan, 2018). Personalized treatment is often needed to control severe asthma These patients require constant attention to avoid exacerbating the disease and the associated unnecessary costs to health and quality of life (Reddel et al, 2009; Lemanske and Busse, 2010; Wang et al, 2018). Increased expression of IL-17A has been documented in the lungs, sputum, BALF, and serum of patients with asthma. This cytokine stimulates a Th2 cell response, airway hyper-reactivity, neutrophil infiltration, and mucus production (Doe et al, 2010; Choy et al, 2015; Chenuet et al, 2017). Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease

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Results

Conclusion