Targeting IL-17/NF-κB/VAChT/Rho-kinase signaling and oxidative stress in exacerbated chronic allergic inflammation: functional and therapeutic implications of IL-17 blockade.

Abstract

Th17 cytokines play a central role in the pathophysiology of chronic allergic pulmonary inflammation, influencing multiple signaling pathways that promote inflammation, oxidative stress, and airway remodeling. We evaluated the modulation of the NF-&#x3ba;B, VAChT, and Rho-kinase signaling pathways, and the effects of anti-interleukin (IL)-17 treatment on airway alterations in a murine model of chronic allergic inflammation were exacerbated by lipopolysaccharide (LPS). We studied airway hyperresponsiveness, inflammation, oxidative stress pathways, tissue remodeling, and the expression of various markers in male BALB/c mice with ovalbumin (OVA)-induced chronic allergic inflammation, with or without anti-IL-17 treatment. Twenty-four hours before the end of the experiment, the OVA-sensitized animals were treated with LPS (OVA-LPS-anti-IL-17). Mice treated with OVA-LPS-anti-IL-17 exhibited decreased elastance of the respiratory system after methacholine challenge, along with reduced infiltration of eosinophils, neutrophils, lymphocytes, and macrophages. Anti-IL-17 treatment also reduced the expression of TNF-&#x3b1;, TARC/eotaxin, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, MMP-9, MMP-12, TIMP-1, TGF-&#x3b2;, iNOS, NF-&#x3ba;B, ROCK1, ROCK2, types I and III collagen, decorin, lumican, biglycan, fibronectin, and 8-iso-PGF2&#x3b1; in airway cells, as well as the mRNA expression of IL-17, VAChT, and arginase 1 in lung tissue, compared to the OVA and OVA-LPS groups (P<0.05), except for TNF-&#x3b1; and actin, which were not reduced compared to the OVA group, and Rrs, actin, and VAChT, which were not reduced compared to the OVA-LPS group. Thus, IL-17 blockade helped control bronchial hyperresponsiveness, modulate the IL-17/NF-&#x3ba;B/VAChT/Rho-kinase pathway, suppress chemokine expression, mitigate airway remodeling, and reduce NO-arginase expression in this asthma mouse model with LPS-induced exacerbation.