Innate Lymphoid Cells Are Required to Induce Airway Hyperreactivity in a Murine Neutrophilic Asthma Model.

Anne-Charlotte Jonckheere,Brecht Steelant,Kaat Dekoster,Ellen Dilissen,Dominique M A Bullens,Greetje Vande Velde,Dominique Schols,Sven F Seys,Lieven J Dupont,Christine Breynaert,Jan L Ceuppens,Jeroen Vanoirbeek,Jonathan Cremer,Tatjana Decaesteker,Rik Schrijvers,Yoichiro Iwakura

doi:10.3389/fimmu.2022.849155

Anne-Charlotte Jonckheere, Brecht Steelant + Show 14 more

Open Access

https://doi.org/10.3389/fimmu.2022.849155

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Abstract

RationaleNon-allergic asthma is driven by multiple endotypes of which neutrophilic and pauci-granulocytic asthma have been best established. However, it is still puzzling what drives inflammation and airway hyperreactivity (AHR) in these patients and how it can be treated effectively. Recently, a potential role of the innate immune system and especially the innate lymphoid cells (ILC) has been proposed.ObjectiveIn this study, we investigated the effects of LPS inhalation on airway inflammation and AHR as a potential model for elucidating the pathogenesis of non-allergic asthma.MethodsWild-type (BALB/c), SCID, IL-17A-/-, and Rag2-/- γC-/- mice were endonasally exposed to lipopolysaccharide (LPS, 2 µg) on four consecutive days. Twenty-four hours after the last exposure, AHR to methacholine was assessed. Cytokine levels and ILC subpopulations were determined in lung tissue. Cellular differential analysis was performed in BAL fluid.Main ResultsIn this study, we developed a murine model for non-allergic neutrophilic asthma. We found that repeated endonasal applications 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 chemokines KC and MIP-2 and cytokines IL-1β, IL-17A, IL-22, and TNF. The adoptive transfer of ILC in Rag2-/- γC-/- mice showed that ILC played a causal role in the induction of AHR in this model. Antagonising IL-1β, but not IL-17A or neutrophils, resulted in a partial reduction in LPS-induced AHR.ConclusionIn conclusion, we report here a murine model for neutrophilic asthma where ILC are required to induce airway hyperreactivity.

Highlights

In this study, we investigated the effects of LPS inhalation on airway inflammation and airway hyperreactivity (AHR) as a potential model for elucidating the pathogenesis of non-allergic asthma
We found that repeated endonasal applications of low-dose LPS in BALB/c mice led to AHR, Bronchoalveolar lavage (BAL) neutrophilia, and a significant increase in lung ILC3 as well as a significant increase in lung chemokines keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 and cytokines IL-1b, IL-17A, IL-22, and tumour necrosis factor (TNF)
We observed a significant increase in the total dendritic cell (DC) population (Figure 2F), which could be attributed to the monocytic-derived DC and the CD11b+ CD103- DCs, in LPS-exposed mice compared to saline-exposed mice

Summary

Introduction

Asthma affects 5% to 15% of the population of all ages [1] It is characterized by chronic airway inflammation and airway hyperreactivity (AHR) and has many phenotypes depending on the age of onset, allergic status, and severity of the disease, with different underlying types of inflammation [1, 2]. Mostly early-onset asthma, can be subdivided into early-onset mild allergic asthma or early-onset moderate to severe allergic asthma [1, 2], showing the heterogeneity of asthma. Both phenotypes are characterized with underlying eosinophilic inflammation, but the severity of the disease differs defined by the GINA guidelines as the level of treatment required to control asthma symptoms and exacerbations [4]. Some patients develop corticosteroid resistance [9], making it an urgent matter to fully understand the pathogenesis of allergic asthma, but of nonallergic asthma, as new therapies can be found to obtain asthma control in patients with corticosteroid resistance

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