CCR3 deficiency shifts adaptive to innate-driven immunity in asthma

Abstract

Background

Because of repeated contact with airborne allergens, patients suffering from allergic asthma experience acute asthma attacks, characterized by shortness of breath, chest tightness, and coughing. The underlying immune response is highly complex and involves various immune cells. Chemokines play a pivotal role in the appropriate relocation of these diverse immune cells, ensuring their directed migration to the site of inflammation, their survival, and their effector functions. In the context of allergic asthma, the chemokine receptor CCR3 is crucially involved in T_H2-mediated airway inflammation by recruiting eosinophils and other immune cells to the site of inflammation. However, more recent studies demonstrate its presence also on mast cells, macrophages, T cells, and dendritic cells.

Objective

We sought to investigate the role of CCR3 in different immune cell types during asthma pathogenesis.

Methods

Human peripheral blood cells collected from healthy controls and asthmatic individuals were analyzed for CCR3 expression. A murine model of asthma was used to compare wild-type and CCR3-deficient mice in the context of airway inflammation.

Results

In a human cohort of asthmatic patients, CCR3 mRNA expression was found induced in PBMCs and positively correlated with decreased lung function and blood eosinophilia. In a murine model of disease, CCR3 was found to be important for the establishment of eosinophilic inflammation. Moreover, CCR3-deficient mice showed impaired cytokine release, resulting in an innate-like mast cell and neutrophil-mediated lung inflammation and reduced T_H2-orchestrated eosinophil-driven asthma. In the absence of CCR3, CD8 T cells underwent phenotypic changes, inhibiting the development of migratory effector memory CD8 T-cell subsets.

Conclusions

Taken together, this work demonstrates the functional involvement of CCR3 in both innate and adaptive immune cells in the lung during asthma pathogenesis.