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

Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32679-32690. doi: 10.1073/pnas.2018497117. Epub 2020 Dec 8.


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.

Keywords: bone marrow chimera; intracerebral hemorrhage; macrophages; microglia; phagocytosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cerebral Hemorrhage / drug therapy
  • Cerebral Hemorrhage / metabolism*
  • Cerebral Hemorrhage / pathology
  • Disease Models, Animal
  • Female
  • Hematoma / drug therapy
  • Hematoma / metabolism*
  • Hematoma / pathology
  • Hemorrhagic Stroke / drug therapy
  • Hemorrhagic Stroke / metabolism*
  • Hemorrhagic Stroke / pathology
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-4 / administration & dosage
  • Interleukin-4 / metabolism*
  • Interleukin-4 / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Morris Water Maze Test / drug effects
  • Phagocytosis / drug effects
  • Phagocytosis / physiology
  • Rotarod Performance Test
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction


  • Il1rl1 protein, mouse
  • Il4 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4