Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
J Neuroinflammation. 2022 Apr 7;19(1):82. doi: 10.1186/s12974-022-02438-6.
Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVβ5/AMPK pathway after ICH.
Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVβ5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function.
Endogenous irisin and its receptor, integrin αVβ5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVβ5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVβ5, p-AMPK and Bcl-2, and decreased the expression of IL-1β, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVβ5 inhibitor cilengitide and AMPK inhibitor dorsomorphin.
This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVβ5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.
神经炎症是脑出血（ICH）后继发性脑损伤发展的关键因素。鸢尾素是一种新发现的肌因子，在实验性缺血性中风中具有很强的神经保护作用。然而，这种肌因子是否能在 ICH 后发挥神经保护作用尚不清楚。本研究旨在探讨鸢尾素治疗对 ICH 后神经炎症和神经元凋亡的影响及其涉及整合素αVβ5/AMPK 通路的潜在机制。
将 285 只成年（8 周龄）雄性 C57BL/6 小鼠随机分为假手术和 ICH 手术组。通过纹状体注射自体血诱导 ICH。ICH 后 30 分钟经鼻给予鸢尾素。为了阐明潜在机制，在给予鸢尾素治疗前给予 cilengitide（一种选择性整合素αVβ5 抑制剂）和 dorsomorphin（一种选择性磷酸化 AMPK 抑制剂）。通过分子、细胞、组织学和功能水平的短期和长期神经行为测试、脑水肿、定量 PCR、western blot、Fluoro-Jade C、TUNEL 和免疫荧光染色来评估神经功能结果。
内源性鸢尾素及其受体整合素αVβ5 在 ICH 后 24 小时增加，达到峰值。鸢尾素治疗后改善了短期和长期的神经功能，减少了 ICH 后的脑水肿。有趣的是，整合素αVβ5 在 ICH 后主要位于小胶质细胞中，鸢尾素治疗后抑制了小胶质细胞/巨噬细胞的促炎极化，促进了抗炎极化。此外，鸢尾素治疗抑制了 ICH 后血肿周围区域中性粒细胞浸润和神经元凋亡细胞死亡。机制上，鸢尾素治疗后显著增加了整合素αVβ5、p-AMPK 和 Bcl-2 的表达，降低了 ICH 后 IL-1β、TNF-α、MPO 和 Bax 的表达。整合素αVβ5 抑制剂 cilengitide 和 AMPK 抑制剂 dorsomorphin 均可消除鸢尾素的神经保护作用。
本研究表明，鸢尾素治疗可改善神经功能缺损，减轻脑水肿，并改善 ICH 后神经炎症和神经元凋亡，至少部分通过整合素αVβ5/AMPK 信号通路。因此，鸢尾素治疗可能为 ICH 的早期治疗提供一种有前途的治疗方法。
