The potential role of innate lymphoid cells in non-allergic neutrophilic asthma model

Abstract

<b>Background:</b> It is still puzzling what drives inflammation and airway hyperreactivity (AHR) in non-allergic asthma with underlying neutrophilic inflammation. Recently, a pathogenic role for the innate lymphoid cells (ILC) has been proposed. <b>Objective:</b> To develop a murine model for non-allergic neutrophilic asthma and to investigate the role of ILC in this model. <b>Methods:</b> BALB/c, IL-17A^−/−, SCID and Rag2^−/−&nbsp;γC^−/− mice were endonasally challenged with lipopolysaccharide (LPS, 2μg) on four consecutive days. On day 5, AHR to methacholine was assessed with the FlexiVent (Scireq). Airway inflammation was studied by analysis of BAL fluid. Cytokine levels and ILC subpopulations were determined in lung tissue. Neutrophils were depleted with an anti-Ly6G mAb (250 μg) injected intraperitoneally 24 hours before the first application with LPS and on day 2 and 4. <b>Results:</b> Endonasal application of low dose LPS in BALB/c mice led to AHR, BAL neutrophilia, and a significant increase in lung ILC3 as well as a significant increase in lung keratinocytes-derived chemokine (KC), MIP-2 and cytokines IL-1β, IL-17A, IL-22 and TNF. Similar experiments in SCID mice (lacking T and B cells) and in Rag2^−/−&nbsp;γC^−/− mice (also lacking ILC) showed that the innate immune system plays a key role in the induction of AHR in this model and that induction of AHR is abrogated in the absence of ILC. Adoptive transfer of ILC in Rag2^−/− γC^−/− mice restored AHR in this model. IL-17A nor neutrophils contributed to LPS-induced AHR. <b>Conclusion:</b> A murine model for neutrophilic asthma was developed revealing a key role of the innate immune system in non-allergic asthma and an essential contribution of ILC to AHR induction.