Theranostics 2018; 8(13):3530-3543. doi:10.7150/thno.24475

Research Paper

CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice

Weirong Fang1,3, Xuan Zhai1,4, Dong Han1, Xiaoxing Xiong1, Tao Wang1, Xun Zeng5, Shucheng He3, Rui Liu3, Masaaki Miyata6, Baohui Xu2, Heng Zhao1✉

1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
2. Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
3. Department of Physiology, China Pharmaceutical University, Nanjing 210009, China
4. Children's Hospital of Chongqing Medical University, Chongqing 400014, China
5. The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
6. Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan

Abstract

Rationale: Peripheral blood monocytes are recruited into the ischemic brain and transform into macrophages after stroke. Nevertheless, the exact role of CCR2-dependent monocytes/macrophages in brain injury after stroke remains elusive.

Methods: We used CCR2 knockout (KO) mice and the CCR2 pharmacological inhibitor, propagermanium (PG), to address the role of CCR2-dependent monocytes/macrophages in the acute stage and neurological functional recovery after middle cerebral artery (MCA) occlusion and reperfusion.

Results: CCR2 KO resulted in smaller infarct size and lower mortality than in wild type (WT) mice, when measured 3 days after stroke. However, from 5 to 28 days after stroke, the KO mice had higher mortality and showed no obvious neurological functional recovery. In addition, WT mice treated with PG had similar stroke outcomes compared with CCR2 KO, as measured by T2 weighted MRI. Flow cytometry and real-time PCR analyses suggest that monocyte-derived macrophages (MoDMs) in the stroke brains mainly polarized to pro-inflammatory macrophages at the early stage, but gradually switched to anti-inflammatory macrophages at 7 days after stroke. In addition, adoptive transfer of anti-inflammatory macrophages into CCR2 KO mice at 4 and 6 days after stroke alleviated mortality and promoted neurological recovery.

Conclusion: CCR2-dependent monocytes/macrophages are a double-edged sword; they worsen acute brain injury, but are essential for neurological recovery by promoting anti-inflammatory macrophage polarization.

Keywords: CCR2, monocytes, functional recovery, ischemic stroke

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How to cite this article:
Fang W, Zhai X, Han D, Xiong X, Wang T, Zeng X, He S, Liu R, Miyata M, Xu B, Zhao H. CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice. Theranostics 2018; 8(13):3530-3543. doi:10.7150/thno.24475. Available from http://www.thno.org/v08p3530.htm