Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh, Pittsburgh, PA 15213.
Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261.
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.
脑出血（ICH）是一种毁灭性的中风形式，影响着全球数百万人。实质血肿引发了一系列反应，导致原发性和继发性脑损伤以及永久性神经功能缺损。小胶质细胞和巨噬细胞进行血肿清除，从而促进 ICH 后的功能恢复。在这里，我们通过调节小胶质细胞/巨噬细胞的功能，阐明白细胞介素（IL）-4/信号转导和转录激活因子 6（STAT6）轴在促进血液和胶原酶注射 ICH 小鼠模型的长期恢复中的关键作用。在这两种 ICH 模型中，STAT6 在小胶质细胞/巨噬细胞中被激活（即，Iba1 细胞中磷酸化 STAT6 的表达增强）。ICH 后，鼻内递送 IL-4 纳米颗粒加速了 STAT6 的激活并促进了血肿的溶解。IL-4 治疗改善了年轻和老年雄性和年轻雌性小鼠的长期功能恢复。相比之下，在两种 ICH 模型中，STAT6 敲除（KO）小鼠的结果比 WT 小鼠更差，并且对 IL-4 治疗的反应更差。骨髓嵌合体小鼠的构建表明，无论是在中枢神经系统还是外周，STAT6 KO 都会加重 ICH 的结果。STAT6 KO 损害了吞噬细胞在 ICH 大脑中和原代培养物中吞噬红细胞的能力。转录分析表明，ICH 后 STAT6 KO 小鼠小胶质细胞/巨噬细胞中白细胞介素 1 受体样 1（ST2）的表达水平较低。ST2 KO 减少了 ICH 后 IL-4 的有益作用。总之，这些数据证实了 IL-4/STAT6/ST2 信号在 ICH 后血肿溶解和功能恢复中的重要性。鼻内 IL-4 治疗作为 ICH 的一种可行的临床治疗方法值得进一步研究。
