Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

Wenting Zhang; Jingyan Zhao; Rongrong Wang; Ming Jiang; Qing Ye; Amanda D. Smith; Jun Chen; Yejie Shi

doi:10.1111/cns.13256

journal article Open Access Nov 07, 2019

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

Wenting Zhang

Jingyan Zhao Rongrong Wang

Ming Jiang

Qing Ye

Amanda D. Smith Jun Chen

Yejie Shi

CNS Neuroscience & Therapeutics Vol. 25 No. 12 pp. 1329-1342 · Wiley

View at Publisher Save 10.1111/cns.13256

Abstract

AbstractAimsBlood‐borne monocytes/macrophages infiltrate the brain in massive numbers after ischemic stroke, but their impact on poststroke brain injury and recovery remains elusive. This study examined the transcriptomic changes in monocytes/macrophages after ischemic stroke and the functional implications of these changes, particularly with regards to the contribution of these cells to the phagocytic clearance of dead/dying cells (efferocytosis) in the poststroke brain.MethodsWe performed whole‐genome RNA sequencing on the monocyte/macrophage population sorted from mouse brain and peripheral blood 5 days after permanent focal cerebral ischemia. In addition, the spatial and temporal profiles of macrophage efferocytosis were examined in vivo by immunohistochemistry 3‐7 days after brain ischemia.ResultsRobust transcriptomic changes occurred in monocytes/macrophages upon infiltrating the poststroke brain. Functional enrichment analysis revealed a transcriptome of brain macrophages that strongly favored efferocytic activity. A large number of efferocytosis‐related genes were upregulated in brain macrophages, the products of which are essential components involved in various steps of efferocytosis, such as chemotaxis, recognition of dead cells, engulfment, and processing of phagosomes. The efferocytic activity of brain macrophages were verified by immunohistochemistry, wherein Iba1‐labeled microglia/macrophages effectively cleared apoptotic neurons in the infarct during the subacute stage after brain ischemia. We also identified PPARγ and STAT6 as potential upstream regulators that shaped this proefferocytic and inflammation‐resolving transcriptome of macrophages in the poststroke brain.ConclusionMacrophages play a crucial role in the phagocytic clearance of dead neurons after ischemic stroke and promote the resolution of inflammation in the brain. Molecular therapies that enhance macrophage efferocytic capability may be promising treatments for ischemic stroke by facilitating inflammation resolution, brain repair, and recovery of neurological functions.

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References

Details

Published: Nov 07, 2019
Vol/Issue: 25(12)
Pages: 1329-1342
License: View

Authors

W

Wenting Zhang

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA

J

Jingyan Zhao

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA

R

Rongrong Wang

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA

M

Ming Jiang

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA

Q

Qing Ye

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA; Geriatric Research, Education and Clinical Center Veterans Affairs Pittsburgh Health Care System Pittsburgh PA USA

A

Amanda D. Smith

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA; Geriatric Research, Education and Clinical Center Veterans Affairs Pittsburgh Health Care System Pittsburgh PA USA

J

Jun Chen

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA; Geriatric Research, Education and Clinical Center Veterans Affairs Pittsburgh Health Care System Pittsburgh PA USA

Y

Yejie Shi

Department of Neurology Pittsburgh Institute of Brain Disorders & Recovery University of Pittsburgh Pittsburgh PA USA; Geriatric Research, Education and Clinical Center Veterans Affairs Pittsburgh Health Care System Pittsburgh PA USA

Funding

American Heart Association Award: 17SDG33630130

U.S. Department of Veterans Affairs Award: BX002495

Cite This Article

Wenting Zhang, Jingyan Zhao, Rongrong Wang, et al. (2019). Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain. CNS Neuroscience & Therapeutics, 25(12), 1329-1342. https://doi.org/10.1111/cns.13256

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

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