Impact of Microglia Polarization and Related Inflammatory Signaling Pathways on Secondary Brain Injury after Intracerebral Hemorrhage

doi:10.3969/j.issn.1673-5765.2023.11.015

Abstract

Abstract: Intracerebral hemorrhage is a severe condition caused by the rupture of blood vessels in the brain parenchyma, and currently lacks an effective treatment. Studies showed that inflammatory reactions play a crucial role in the brain damage that occurs as a result of intracerebral hemorrhage. Microglia, present at the site of bleeding, are rapidly recruited and activated, transitioning between pro-inflammatory and anti-inflammatory states. The polarization state of microglia can be altered by various signaling pathways, thus regulating the extent of brain damage. This suggests that microglia have a complex mechanism of action in the pathological process of secondary brain injury following intracerebral hemorrhage. Pro-inflammatory microglia release inflammatory factors that contribute to damage in nerve cells and nervous tissue, while anti-inflammatory microglia release chemokines, brain-derived neurotrophic factors, and anti-inflammatory mediators to induce the migration of microglia towards the lesion site. These microglia then phagocytose harmful molecules and cell debris, reducing inflammatory damage and promoting inflammation resolution, tissue repair, and nerve regeneration. However, the dynamic changes and mechanisms underlying microglial polarization after intracerebral hemorrhage have not been fully elucidated. Therefore, there is widespread interest in studying the regulatory molecules and signaling pathways involved in microglial polarization after intracerebral hemorrhage, as they may serve as potential targets for the treatment of intracerebral hemorrhage.

Key words: Intracerebral hemorrhage; Microglia; Secondary brain injury; Signaling pathway

摘要： 脑出血是一种由脑实质血管破裂引起的严重疾病，目前尚无有效的治疗方法。研究表明炎症反应在脑出血继发性脑损伤中发挥了重要作用。在出血部位，小胶质细胞被迅速招募并激活，且在促炎型与抑炎型之间动态转变，不同的信号通路可以改变小胶质细胞极化的状态，从而对脑损伤起到调控作用，这提示了小胶质细胞在脑出血继发脑损伤的病理过程中具有复杂的作用机制。促炎型小胶质细胞释放的各种炎症因子介导神经细胞和神经组织的炎症损伤；抑炎型小胶质细胞释放趋化因子、脑源性神经营养因子、抗炎介质等诱导小胶质细胞向病变方向迁移，吞噬有害分子和细胞碎片，减轻炎症损伤，促进炎症消退、组织修复及神经再生。然而，目前对于小胶质细胞极化在脑出血后的动态变化及机制尚未完全阐明，故对参与脑出血小胶质细胞极化的相关调控分子以及信号通路的研究已引起了广泛关注，有望成为脑出血治疗的潜在靶点。

关键词: 脑出血; 小胶质细胞; 继发性脑损伤; 信号通路

KONG Demin, ZOU Wei. Impact of Microglia Polarization and Related Inflammatory Signaling Pathways on Secondary Brain Injury after Intracerebral Hemorrhage[J]. Chinese Journal of Stroke, 2023, 18(11): 1315-1323.

孔德敏, 邹伟. 脑出血后小胶质细胞极化及其相关炎症信号通路对继发性脑损伤的影响[J]. 中国卒中杂志, 2023, 18(11): 1315-1323.

References

[1] TOYODA K，KOGA M，YAMAMOTO H，et al. Clinical outcomes depending on acute blood pressure after cerebral hemorrhage[J]. Ann Neurol，2019，85（1）：105-113.
[2] SCHRAG M，KIRSHNER H. Management of intracerebral hemorrhage：JACC focus seminar[J]. J Am Coll Cardiol，2020，75（15）：1819-1831.
[3] WANG Z，ZHOU F，DOU Y，et al. Melatonin alleviates intracerebral hemorrhage-induced secondary brain injury in rats via suppressing apoptosis，inflammation，oxidative stress，DNA damage，and mitochondria injury[J]. Transl Stroke Res，2018，9（1）：74-91.
[4] MAGID-BERNSTEIN J，GIRARD R，POLSTER S，et al. Cerebral hemorrhage：pathophysiology，treatment，and future directions[J]. Circ Res，2022，130（8）：1204-1229.
[5] ELDAHSHAN W，FAGAN S C，ERGUL A. Inflammation within the neurovascular unit：focus on microglia for stroke injury and recovery[J/OL]. Pharmacol Res，2019，147：104349[2023-01-05]. https://doi.org/10.1016/j.phrs.2019.104349.
[6] BIAN Z L，GONG Y D，HUANG T，et al. Deciphering human macrophage development at single-cell resolution[J]. Nature，2020，582（7813）：571-576.
[7] YANG G Q，FAN X H，MAZHAR M，et al. Neuroinflammation of microglia polarization in intracerebral hemorrhage and its potential targets for intervention[J/OL]. Front Mol Neurosci，2022，15：1013706[2023-01-05]. https://doi.org/10.3389/fnmol.2022.1013706.
[8] ARONOWSKI J，ZHAO X R. Molecular pathophysiology of cerebral hemorrhage：secondary brain injury[J]. Stroke，2011，42（6）：1781-1786.
[9] BABI M A，JAMES M L. Peri-hemorrhagic edema and secondary hematoma expansion after intracerebral hemorrhage：from benchwork to practical aspects[J/OL]. Front Neurol，2017，8：4[2023-01-11]. https://doi.org/10.3389/fneur.2017.00004.
[10] BAI Q，XUE M Z，YONG V W. Microglia and macrophage phenotypes in intracerebral haemorrhage injury：therapeutic opportunities[J]. Brain，2020，143（5）：1297-1314.
[11] CHEN Y H，CHEN S P，CHANG J B，et al. Perihematomal edema after intracerebral hemorrhage：an update on pathogenesis，risk factors，and therapeutic advances[J/OL]. Front Immunol，2021，12：740632[2023-01-11]. https://doi.org/10.3389/fimmu.2021.740632.
[12] CHANG C F，MASSEY J，OSHEROV A，et al. Bexarotene enhances macrophage erythrophagocytosis and hematoma clearance in experimental intracerebral hemorrhage[J]. Stroke，2020，51（2）：612-618.
[13] LEITNER G R，WENZEL T J，MARSHALL N，et al. Targeting Toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders[J]. Expert Opin Ther Targets，2019，23（10）：865-882.
[14] WANG Z，WU L Y，YOU W C，et al. Melatonin alleviates secondary brain damage and neurobehavioral dysfunction after experimental subarachnoid hemorrhage：possible involvement of TLR4-mediated inflammatory pathway[J]. J Pineal Res，2013，55（4）：399-408.
[15] DRESSELHAUS E C，MEFFERT M K. Cellular specificity of NF-κB function in the nervous system[J/OL]. Front Immunol，2019，10：1043[2023-01-11]. https://doi.org/10.3389/fimmu.2019.01043.
[16] LIU M，XU Z P，WANG L，et al. Cottonseed oil alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte[J/OL]. J Neuroinflammation，2020，17（1）：270[2023-01-10]. https://doi.org/10.1186/s12974-020-01946-7.
[17] LIU D L，ZHAO L X，ZHANG S，et al. Peroxiredoxin 1-mediated activation of TLR4/NF-κB pathway contributes to neuroinflammatory injury in intracerebral hemorrhage[J/OL]. Int Immunopharmacol，2016，41：82-89[2023-01-11]. https://doi.org/10.1016/j.intimp.2016.10.025.
[18] LAN X，HAN X N，LI Q，et al. Pinocembrin protects hemorrhagic brain primarily by inhibiting Toll-like receptor 4 and reducing M1 phenotype microglia[J/OL]. Brain Behav Immun，2017，61：326-339[2023-01-11]. https://doi.org/10.1016/j.bbi.2016.12.012.
[19] WU X，FU S M，LIU Y，et al. NDP-MSH binding
melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice[J/OL]. J Neuroinflammation，2019，16（1）：192[2023-01-11]. https://doi.org/10.1186/s12974-019-1591-4.
[20] MONNEY L，SABATOS C A，GAGLIA J L，et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease[J]. Nature，2002，415（6871）：536-541.
[21] YU A Y，ZHANG X J，LI M，et al. Tim-3 enhances brain inflammation by promoting M1 macrophage polarization following intracerebral hemorrhage in mice[J/OL]. Int Immunopharmacol，2017，53：143-148[2023-01-11]. https://doi.org/10.1016/j.intimp.2017.10.023.
[22] JOHN S，MISHRA R. Galectin-9：from cell biology to complex disease dynamics[J]. J Biosci，2016，41（3）：507-534.
[23] LIANG T Y，MA C，WANG T Y，et al. Galectin-9 promotes neuronal restoration via binding TLR-4 in a rat intracerebral hemorrhage model[J]. Neuromolecular Med，2021，23（2）：267-284.
[24] CHEN Z Q，YU H，LI H Y，et al. Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats[J]. CNS Neurosci Ther，2019，25（6）：674-684.
[25] OHNISHI M，KATSUKI H，FUJIMOTO S，et al. Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury[J]. Exp Neurol，2007，206（1）：43-52.
[26] CAI Y，CHO G S，JU C，et al. Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation[J]. J Immunol，2011，187（3）：1314-1321.
[27] CHEN S P，ZUO Y C，HUANG L，et al. The MC4 receptor agonist RO27-3225 inhibits NLRP1-dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage[J]. Br J Pharmacol，2019，176（9）：1341-1356.
[28] YANG H，GAO X J，LI Y J，et al. Minocycline reduces intracerebral hemorrhage-induced white matter injury in piglets[J]. CNS Neurosci Ther，2019，25（10）：1195-1206.
[29] CHAMAILLARD M，HASHIMOTO M，HORIE Y，et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid[J]. Nat Immunol，2003，4（7）：702-707.
[30] CARNEIRO L A，MAGALHAES J G，TATTOLI I，et al. NOD-like proteins in inflammation and disease[J]. J Pathol，2008，214（2）：136-148.
[31] HARIKRISHNAN H，JANTAN I，HAQUE M A，et al. Anti-inflammatory effects of hypophyllanthin and niranthin through downregulation of NF-κB/MAPKs/PI3K-AKt signaling pathways[J]. Inflammation，2018，41（3）：984-995.
[32] LE BOURHIS L，BENKO S，GIRARDIN S E. Nod1 and Nod2 in innate immunity and human inflammatory disorders[J/OL]. Biochem Soc Trans，2007，35（Pt 6）：1479-1484[2023-01-11]. https://doi.org/10.1042/BST0351479.
[33] WANG M，YE X C，HU J X，et al. NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice[J/OL]. J Neuroinflammation，2020，17（1）：364[2023-01-11]. https://doi.org/10.1186/s12974-020-02015-9.
[34] 袁志俊，何晓英，李娇红，等. JAK2/STAT3通路对大鼠脑出血周围组织VEGF165等的保护作用[J]. 中西医结合心脑血管病杂志，2018，16（6）：708-711.
YUAN Z J，HE X Y，LI J H，et al. The neuroprotective effect of VEGF 165 on cerebral hemorrhage through the JAK2/STAT3 signaling pathway[J]. Chin J Integrat Med Cardio-/Cerebrovasc Dis，2018，16（6）：708-711.
[35] ZHAO X R，ZHANG Y J，STRONG R，et al. Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit，iNOS，and COX-2 expression[J]. J Neurochem，2007，101（3）：652-663.
[36] JI X C，SHI Y J，ZHANG Y，et al. Reducing suppressors of cytokine signaling-3（SOCS3）expression promotes M2 macrophage polarization and functional recovery after intracerebral hemorrhage[J/OL]. Front Neurol，2020，11：586905[2023-01-11]. https://doi.org/10.3389/fneur.2020.586905.
[37] YANG Q L，LANGSTON J C，TANG Y，et al. The role of tyrosine phosphorylation of protein kinase C delta in infection and inflammation[J/OL]. Int J Mol Sci，2019，20（6）：1498[2023-01-11]. https://doi.org/10.3390/ijms20061498.
[38] ZHONG X M，CHEN B，YANG L，et al. Molecular and physiological roles of the adaptor protein CARD9 in immunity[J/OL]. Cell Death Dis，2018，9（2）：52[2023-01-11]. https://doi.org/10.1038/s41419-017-0084-6.
[39] LU Q，LIU R，SHERCHAN P，et al. TREM（triggering receptor expressed on myeloid cells）-1 inhibition attenuates neuroinflammation via PKC（protein kinase c）δ/CARD9（caspase recruitment domain family member 9）signaling pathway after intracerebral hemorrhage in mice[J]. Stroke，2021，52（6）：2162-2173.
[40] HUANG H T，LIU H W，YAN R Z，et al. PI3K/Akt and ERK/MAPK signaling promote different aspects of neuron survival and axonal regrowth following rat facial nerve axotomy[J]. Neurochem Res，2017，42（12）：3515-3524.
[41] DENG S X，JIN P，SHERCHAN P，et al. Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice[J/OL]. J Neuroinflammation，2021，18（1）：62[2023-01-11]. https://doi.org/10.1186/s12974-021-02112-3.
[42] ZHAO M M，GAO J L，ZHANG Y N，et al. Elevated miR-29a contributes to axonal outgrowth and neurological recovery after intracerebral hemorrhage via targeting PTEN/PI3K/Akt pathway[J]. Cell Mol Neurobiol，2021，41（8）：1759-1772.
[43] ZHAO M M，GAO J L，CUI C M，et al. Inhibition of PTEN ameliorates secondary hippocampal injury and cognitive deficits after intracerebral hemorrhage：involvement of AKT/FoxO3a/ATG-mediated autophagy[J/OL]. Oxid Med Cell Longev，2021，2021：5472605[2023-01-11]. https://doi.org/10.1155/2021/5472605.
[44] HU L T，ZHANG H Y，WANG B Y，et al. MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase[J/OL]. Int Immunopharmacol，2019，76：105887[2023-01-11]. https://doi.org/10.1016/j.intimp.2019.105887.
[45] DENG S X，SHERCHAN P，JIN P，et al. Recombinant CCL17 enhances hematoma resolution and activation of CCR4/ERK/Nrf2/CD163 signaling pathway after intracerebral hemorrhage in mice[J]. Neurotherapeutics，2020，17（4）：1940-1953.
[46] DENG S X，LIU S P，JIN P，et al. Albumin reduces oxidative stress and neuronal apoptosis via the ERK/NRF2/HO-1 pathway after intracerebral hemorrhage in rats[J/OL]. Oxid Med Cell Longev，2021，2021：8891373[2023-01-11]. https://doi.org/10.1155/2021/8891373.
[47] 陈小红. 从BDNF/TrkB信号通路探讨安脑平冲方对脑出血大鼠神经保护的作用[D]. 长沙：湖南中医药大学，2022.
CHEN X H. Exploring the neuroprotective effect of Annaopingchong formula on cerebral hemorrhage rats through the BDNF/TrkB signaling pathway[D]. Changsha：Hunan University of Chinese Medicine，2022.
[48] MIAO H S，LI R M，HAN C，et al. Minocycline promotes posthemorrhagic neurogenesis via M2 microglia polarization via upregulation of the TrkB/BDNF pathway in rats[J]. J Neurophysiol，2018，120（3）：1307-1317.
[49] CHENG J，TANG J C，PAN M X，et al. l-lysine confers neuroprotection by suppressing inflammatory response via microRNA-575/PTEN signaling after mouse intracerebral hemorrhage injury[J/OL]. Exp Neurol，2020，327：113214[2023-01-11]. https://doi.org/10.1016/j.expneurol.2020.113214.
[50] 张瑛，高晓峰，郭纯，等. 基于PPARγ信号通路探讨安脑平冲方极化M2型小胶质细胞减轻脑出血后神经炎症的作用机制[J]. 湖南中医药大学学报，2023，43（3）：405-412.
ZHANG Y，GAO X F，GUO C，et al. Mechanism of Annao Pingchong Formula on polarization of M2 microglia in alleviating neuroinflammation after intracerebral hemorrhage based on PPARγ signaling pathway[J]. J Hunan Univ Chin Med，2023，43（3）：405-412.
[51] XU C R，CHEN H J，ZHOU S J，et al. Pharmacological activation of RXR-α promotes hematoma absorption via a PPAR-γ-dependent pathway after intracerebral hemorrhage[J]. Neurosci Bull，2021，37（10）：1412-1426.
[52] LAN X，HAN X，LI Q，et al. Modulators of microglial activation and polarization after intracerebral haemorrhage[J]. Nat Rev Neurol，2017，13（7）：420-433.
[53] ZHANG R Y，YONG V W，XUE M Z. Revisiting minocycline in intracerebral hemorrhage：mechanisms and clinical translation[J/OL]. Front Immunol，2022，13：844163[2023-01-11]. https://doi.org/10.3389/fimmu.2022.844163.
[54] 董伟，张利，王彦，等. 高血压脑出血术后应用依达拉奉佑崁醇对患者细胞炎症因子及神经功能的影响[J]. 中国煤炭工业医学杂志，2021，24（6）：618-623.
DONG W，ZHANG L，WANG Y，et al. Effect of treatment of hypertensive intracerebeal hemorrhage with edaravoneol on cytoinflammatory factors and neurological function in patients[J]. Chin J Coal Industry Med，2021，24（6）：618-623.
[55] 邹经，占克斌. 芬戈莫德在脑血管疾病中的炎症免疫调节作用[J]. 神经损伤与功能重建，2019，14（4）：188-190.
ZOU J，ZHAN K B. The inflammatory and immune regulatory effects of Fingolimod in cerebrovascular diseases[J]. Neural Injury and Functional Reconstruction，2019，14（4）：188-190.
[56] 晚丽，李作孝. 依达拉奉右莰醇通过抑制TLR4/NF-κB信号通路减轻实验性自身免疫性脑脊髓炎小鼠炎症反应[J]. 天津医药，2022，50（5）：471-475.
WAN L，LI Z X. Edaravone dexborneol reduces inflammation in mice with experimental autoimmune encephalomyelitis by inhibiting TLR4/NF-κB signaling pathway[J]. Tianjin Med J，2022，50（5）：471-475.