Title

IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

DOI

10.1073/pnas.2018497117

Authors

Jing Xu, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Zhouqing Chen, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Fang Yu, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Huan Liu, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Cheng Ma, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Di Xie, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Xiaoming Hu, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Rehana K. Leak, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282.
Sherry H. Chou, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
R Anne Stetler, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Yejie Shi, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Jun Chen, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Michael V. Bennett, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461 michael.bennett@einstein.yu.edu nju_neurosurgery@163.com.
Gang Chen, Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213; michael.bennett@einstein.yu.edu nju_neurosurgery@163.com.

Document Type

Journal Article

Publication Date

12-22-2020

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

117

Issue

51

First Page

32679

Last Page

32690

Keywords

bone marrow chimera, intracerebral hemorrhage, macrophages, microglia, phagocytosis

Abstract

Intracerebral hemorrhage (ICH) is a devastating form of stroke affecting millions of people worldwide. Parenchymal hematoma triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia and macrophages carry out hematoma clearance, thereby facilitating functional recovery after ICH. Here, we elucidate a pivotal role for the interleukin (IL)-4)/signal transducer and activator of transcription 6 (STAT6) axis in promoting long-term recovery in both blood- and collagenase-injection mouse models of ICH, through modulation of microglia/macrophage functions. In both ICH models, STAT6 was activated in microglia/macrophages (i.e., enhanced expression of phospho-STAT6 in Iba1 cells). Intranasal delivery of IL-4 nanoparticles after ICH hastened STAT6 activation and facilitated hematoma resolution. IL-4 treatment improved long-term functional recovery in young and aged male and young female mice. In contrast, STAT6 knockout (KO) mice exhibited worse outcomes than WT mice in both ICH models and were less responsive to IL-4 treatment. The construction of bone marrow chimera mice demonstrated that STAT6 KO in either the CNS or periphery exacerbated ICH outcomes. STAT6 KO impaired the capacity of phagocytes to engulf red blood cells in the ICH brain and in primary cultures. Transcriptional analyses identified lower level of IL-1 receptor-like 1 (ST2) expression in microglia/macrophages of STAT6 KO mice after ICH. ST2 KO diminished the beneficial effects of IL-4 after ICH. Collectively, these data confirm the importance of IL-4/STAT6/ST2 signaling in hematoma resolution and functional recovery after ICH. Intranasal IL-4 treatment warrants further investigation as a clinically feasible therapy for ICH.

Open Access

Green Accepted

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