Volume 28, No 3, Mar 2018
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 28 Issue 3, March 2018: 323-335
ORIGINAL ARTICLES
Eosinophil-derived CCL-6 impairs hematopoietic stem cell homeostasis
Chao Zhang1, *, Weiwei Yi2, *, Fei Li1, Xufei Du1, Hu Wang2, 3, Ping Wu4, Chao Peng4, Man Luo1, Wen Hua1, Catherine CL Wong4, James J Lee5, Wen Li1, Zhihua Chen1, Songmin Ying1, 6, 7, Zhenyu Ju2, 3, Huahao Shen1, 8
1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Institute of Respiratory Diseases, Hangzhou, Zhejiang 310009, China;
2Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China;
3 Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China;
4 National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201210, China;
5 Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Arizona 85259, USA;
6 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;
7 Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China;
8 State Key Lab of Respiratory Disease, Guangzhou, Guangdong 510120, China
Correspondence: Huahao Shen,E-mail: huahaoshen@zju.edu.cn; Zhenyu Ju,E-mail: zhenyuju@163.com; Songmin Ying(E-mail: yings@zju.edu.cn)
Eosinophils (Eos) have been long considered as end-stage effector cells in the hierarchical hematopoietic system. Numerous lines of evidence have suggested that Eos are multifunctional leukocytes with respect to the initiation, propagation and regulation of various inflammatory or immune reactions, especially in allergic diseases. Recent studies have shown that Eos are also required for maintenance of bone marrow plasma cells and differentiation of B cells. However, it remains unclear whether Eos contributes to regulation of hematopoietic stem cell (HSC) homeostasis. Here, we demonstrate that Eos disrupt HSC homeostasis by impairing HSC quiescence and reconstitution ability in wild-type mice following ovalbumin (OVA) challenge and even by causing bone marrow HSC failure and exhaustion in Cd3δ-Il-5 transgenic mice. The impaired maintenance and function of HSCs were associated with Eos-induced redox imbalance (increased oxidative phosphorylation and decreased anti-oxidants levels). More importantly, using mass spectrometry, we determined that CCL-6 is expressed at a high level under eosinophilia. We demonstrate that CCL-6 is Eos-derived and responsible for the impaired HSC homeostasis. Interestingly, blockage of CCL-6 with a specific neutralizing antibody, restored the reconstitution ability of HSCs while exacerbating eosinophilia airway inflammation in OVA-challenged mice. Thus, our study reveals an unexpected function of Eos/CCL-6 in HSC homeostasis.
10.1038/cr.2018.2
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