New targets for asthma inflammation treatment

As one of the most common chronic diseases, there are nearly 400 million asthma patients worldwide, and more than 60 million asthma patients in China. In this concern, prevention and treatment of asthma is in the spotlight of public health and medical care issues. More than half of asthma patients are caused by type 2 immune response dominated by allergic-induced TH2 cells. Many immune cell components including eosinophils play important roles in allergic inflammation. The main pathological features are eosinophils infiltration, mucus high secretion and airway hyperresponsiveness.

The research team led by Prof. SHEN Huahao from the Second Affiliated Hospital of the Zhejiang University School of Medicine and Prof. YING Songmin from the School of Basic Medical Sciences an article entitled Eosinophil-derived chemokine (hCCL15/23, mCCL6) interacts with CCR1 to promote eosinophilic airway inflammation in Signal Transduction and Targeted Therapy.

Schematic diagram: CCL6-CCR1 signaling axis regulates asthma inflammation.

In this study, they established chemokine CCL6 knockout mice for the first time and explored the functional role of eosinophil-derived mCCL6 in the pathology of allergic inflammation. It is confirmed that CCL6 interacts with G protein-coupled receptor (GPCR) CCR1, constituting a feedforward loop of asthma exacerbation. Targeting CCR1 can inhibit the differentiation of eosinophils and airway inflammation in vivo and in vitro, revealing that targeting the CCL6-CCR1 axis can be a new therapeutic target for clinical treatment of asthma point.

Chemokines CCL6/15/23 belong to the NC6 family. Prof. SHEN’s team found that CCL6/15/23 are mainly secreted by eosinophils and confirmed that CCL6 can directly activate CCR1 and its downstream signaling pathways. Lack of CCL6 in mice can significantly alleviate the pathological manifestations of eosinophil infiltration, airway inflammation, and mucus hypersecretion in asthma inflammation, and the differentiation of eosinophils in the bone marrow is also inhibited. The human ortholog of CCL6, CCL15 and 23, are also significantly increased in the plasma of asthma patients, supporting the clinical significance of this finding. 

The researchers also found that CCL6 activates CCR1 coupled Gαi protein and phosphorylation of downstream signaling pathway proteins, thereby promoting HSC activation and providing reliable evidence for the function of CCL6-CCR1 signaling axis in asthma. These findings not only provide new insights into the regulatory role of eosinophils in asthma inflammation, but also a therapeutic target of chemokines and receptors in asthma treatment.

Leaders of research team: Prof. YING Songmin (left), Prof. SHEN Huahao (front).

Source: School of Medicine