Attenuation of antigen-induced airway hyperresponsiveness and inflammation in CXCR3 knockout mice

Yi Lin,Ruolan Xiang,Jinming Gao,Wexun Zhou,Hongmei Piao,Lei Jiang,Zijian Guo,Yu Xiao,Haibo Yan,Bao Lu,Kewu Huang,Huaxia Chen

doi:10.1186/1465-9921-12-123

Abstract

BackgroundCD8+ T cells participate in airway hyperresponsiveness (AHR) and allergic pulmonary inflammation that are characteristics of asthma. CXCL10 by binding to CXCR3 expressed preferentially on activated CD8+ T cells, attracts T cells homing to the lung. We studied the contribution and limitation of CXCR3 to AHR and airway inflammation induced by ovalbumin (OVA) using CXCR3 knockout (KO) mice.MethodsMice were sensitized and challenged with OVA. Lung histopathological changes, AHR, cellular composition and levels of inflammatory mediators in bronchoalveolar lavage (BAL) fluid, and lungs at mRNA and protein levels, were compared between CXCR3 KO mice and wild type (WT) mice.ResultsCompared with the WT controls, CXCR3 KO mice showed less OVA-induced infiltration of inflammatory cells around airways and vessels, and less mucus production. CXCR3 KO mice failed to develop significant AHR. They also demonstrated significantly fewer CD8+ T and CD4+ T cells in BAL fluid, lower levels of TNFα and IL-4 in lung tissue measured by real-time RT-PCR and in BAL fluid by ELISA, with significant elevation of IFNγ mRNA and protein expression levels.ConclusionsWe conclude that CXCR3 is crucial for AHR and airway inflammation by promoting recruitment of more CD8+ T cells, as well as CD4+ T cells, and initiating release of proinflammatory mediators following OVA sensitization and challenge. CXCR3 may represent a novel therapeutic target for asthma.

Highlights

Asthma is characterized by the persistence of chronic airway inflammation, which further leads to airway hyperresponsiveness (AHR), and mucus hypersecretion
A small-molecule antagonist for both CXCR3 and CCR5 has been reported to alleviate some asthmatic responses after antigen exposure, such as AHR and lung inflammation [14]. These findings indicate that CXCR3/CXCL10 axis may play a pivotal role in the pathogenesis of asthma through recruitment of T cells, as well as other inflammatory cells, into airways and lung parenchyma
Airway inflammation in OVA-sensitized and -exposed mice To determine whether CXCR3 depletion affects the antigen-induced infiltration of inflammatory cells into airways, we estimated the cell subpopulations in bronchoalveolar lavage (BAL) fluid following antigen sensitization and challenge

Summary

Introduction

Asthma is characterized by the persistence of chronic airway inflammation, which further leads to airway hyperresponsiveness (AHR), and mucus hypersecretion. A key step in the initiation and progression of asthma is the persistent recruitment of inflammatory cells into the airways of asthma patients in response to allergen, a process closely regulated by a variety of chemokines [5]. The expression of distinct chemokine receptors on infiltrating cell populations, especially on lymphocytes and eosinophils which are highly implicated in the pathogenesis of asthma, may represent a novel target for attenuating the influx of these inflammatory cells into the airways during the asthmatic process [6,7]. CD8+ T cells participate in airway hyperresponsiveness (AHR) and allergic pulmonary inflammation that are characteristics of asthma. We studied the contribution and limitation of CXCR3 to AHR and airway inflammation induced by ovalbumin (OVA) using CXCR3 knockout (KO) mice

Methods

Results

Conclusion