Theranostics 2020; 10(5):2422-2435. doi:10.7150/thno.37106 This issue

Research Paper

CD226 deletion improves post-infarction healing via modulating macrophage polarization in mice

Jun Li1*, Yun Song2*, Jing-Yi Jin2, Guo-Hua Li1, Yong-Zheng Guo1, Hong-Yu Yi2, Jin-Rui Zhang2, Ya-Jie Lu1, Jing-Long Zhang1, Cong-Ye Li3, Chao Gao3, Lu Yang1, Feng Fu1, Fu-lin Chen4, Shu-Miao Zhang1, Min Jia1, Guo-Xu Zheng1, Jian-Ming Pei1✉, Li-Hua Chen2,4✉

1. Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, School of Basic Medicine, Fourth Military Medical University, No.169, West Changle Road, Xi'an, 710032, China.
2. Department of Immunology, School of Basic Medicine, Fourth Military Medical University, No.169, West Changle Road, Xi'an, 710032, China.
3. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, No.169, West Changle Road, Xi'an, 710032, China.
4. Faculty of Medicine, Northwest University, No.229, Taibai Bei Road, Xi'an, 710069, China
*Jun Li and Yun Song contributed equally to this article.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li J, Song Y, Jin JY, Li GH, Guo YZ, Yi HY, Zhang JR, Lu YJ, Zhang JL, Li CY, Gao C, Yang L, Fu F, Chen Fl, Zhang SM, Jia M, Zheng GX, Pei JM, Chen LH. CD226 deletion improves post-infarction healing via modulating macrophage polarization in mice. Theranostics 2020; 10(5):2422-2435. doi:10.7150/thno.37106. Available from https://www.thno.org/v10p2422.htm

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Abstract

Graphic abstract

Macrophages are essential for wound repair after myocardial infarction (MI). CD226, a member of immunoglobulin superfamily, is expressed on inflammatory monocytes, however, the role of CD226 in infarct healing and the effect of CD226 on macrophage remain unknown.

Methods: Wild type and CD226 knockout (CD226 KO) mice were subjected to permanent coronary ligation. CD226 expression, cardiac function and ventricular remodeling were evaluated. Profile of macrophages, myofibroblasts, angiogenesis and monocytes mobilization were determined.

Results: CD226 expression increased in the infarcted heart, with a peak on day 7 after MI. CD226 KO attenuated infarct expansion and improved infarct healing after MI. CD226 deletion resulted in increased F4/80+ CD206+ M2 macrophages and diminished Mac-3+ iNOS+ M1 macrophages accumulation in the infarcted heart, as well as enrichment of α-smooth muscle actin positive myofibroblasts and Ki67+ CD31+ endothelial cells, leading to increased reparative collagen deposition and angiogenesis. Furthermore, CD226 deletion restrained inflammatory monocytes mobilization, as revealed by enhanced retention of Ly6Chi monocytes in the spleen associated with a decrease of Ly6Chi monocytes in the peripheral blood, whereas local proliferation of macrophage in the ischemic heart was not affected by CD226 deficiency. In vitro studies using bone marrow-derived macrophages showed that CD226 deletion potentiated M2 polarization and suppressed M1 polarization.

Conclusion: CD226 expression is dramatically increased in the infarcted heart, and CD226 deletion improves post-infarction healing and cardiac function by favoring macrophage polarization towards reparative phenotype. Thus, inhibition of CD226 may represent a novel therapeutic approach to improve wound healing and cardiac function after MI.

Keywords: macrophage, myocardial infarction, healing, inflammation, polarization