IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice
- 8 December 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (51), 32679-32690
- https://doi.org/10.1073/pnas.2018497117
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.Keywords
This publication has 50 references indexed in Scilit:
- Transcriptional regulation by STAT6Immunologic Research, 2011
- Inhibition of Suppressive T Cell Factor 1 (TCF-1) Isoforms in Naive CD4+ T Cells Is Mediated by IL-4/STAT6 SignalingOnline Journal of Public Health Informatics, 2011
- The health loss from ischemic stroke and intracerebral hemorrhage: evidence from the North East Melbourne Stroke Incidence Study (NEMESIS)Health and Quality of Life Outcomes, 2010
- Principles, Techniques, and Applications of T2*-based MR Imaging and Its Special ApplicationsRadioGraphics, 2009
- Hematoma Resolution as a Therapeutic Target: The Role of Microglia/MacrophagesStroke, 2008
- Intracerebral Hemorrhage Models in Rat: Comparing Collagenase to Blood InfusionJournal of Cerebral Blood Flow & Metabolism, 2007
- Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in AdultsStroke, 2007
- Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhageBrain, 2007
- Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trialThe Lancet, 2005
- Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality.Stroke, 1993