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

Jing Xu, Zhouqing Chen, Fang Yu, Huan Liu, Cheng Ma, Di Xie, Xiaoming Hu, Rehana K. Leak, Sherry H.Y. Chou, Anne Stetler R. Anne Stetler, Yejie Shi, Jun Chen, Michael V.L. Bennett, Gang Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 bloodand 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.

Original languageEnglish (US)
Pages (from-to)32679-32690
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number51
DOIs
StatePublished - Dec 22 2020
Externally publishedYes

Keywords

  • Bone marrow chimera
  • Intracerebral hemorrhage
  • Macrophages
  • Microglia
  • Phagocytosis

ASJC Scopus subject areas

  • General

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