Eosinophil-derived chemokine (hCCL15/23, mCCL6) interacts with CCR1 to promote eosinophilic airway inflammation

Xufei Du,Min Zhang,Na Li,Xueqin Zhan,Zhenyu Ju,Yicheng He,Wen Li,Zhehua Shao,Fei Li,Songmin Ying,Chao Zhang,Huahao Shen,Huaqiong Huang,Zhihua Chen

doi:10.1038/s41392-021-00482-x

Abstract

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.

Highlights

Asthma is among the most common chronic diseases, affecting 1–18% of the population in different countries with an increasing prevalence.[1]
Elevated hCCL23 and hCCL15 ortholog levels in asthma patients To explore the clinical relevance of hCCL23/hCCL15 and the eosinophil count in allergic asthma, we analyzed blood samples from 31 asthma patients with acute attack and 30 healthy controls
Upon analyzing the lineages associated with eosinophilopoiesis, including CMPs, granulocyte-macrophage progenitor cells (GMPs), megakaryocyte-erythroid progenitor cells (MEPs) (Fig. 4f, g), and eosinophil progenitor cells (EoPs) (Fig. 4h, i), we found that mCCL6 deficiency abolished the increases in hematopoietic stem and progenitor cell populations in the bone marrow

Summary

Introduction

Asthma is among the most common chronic diseases, affecting 1–18% of the population in different countries with an increasing prevalence.[1] A high blood eosinophil count is a predictive risk factor and biomarker of asthma exacerbations.[2,3]. Eosinophils differentiate from HSCs and mature in the bone marrow,[4] are recruited to inflammatory sites, and release an array of cytokines, chemokines, or granules to mediate the airway pathological response, mucus hypersecretion, airway remodeling, and airway hyperresponsiveness.[5,6] Directly targeting the eosinophil differentiation process is an effective therapeutic strategy to control clinical symptoms of asthma and reduce exacerbations.[7,8,9,10,11]. Active eosinophils produce cytokines, such as interleukin (IL)-4, IL-13, C-C chemokine ligand 5 (CCL5), and granulocyte-macrophage colonystimulating factor (GM-CSF), and regulate dendritic cells and T helper type 2 (TH2) effector cells in pulmonary immune responses.[12,13,14] Eosinophils secrete granules, including eosinophil peroxidase (EPX), eosinophil granule major basic proteins, eosinophil cationic protein, and eosinophil-derived neurotoxin, which directly contribute to asthmatic pathology.[15,16]

Methods

Results

Conclusion