Research progress on the role of complement in ischemic stroke

doi:10.11817/j.issn.1673-9248.2024.04.015

Abstract

Abstract:

Ischemic stroke presents significant morbidity and disability, with limited therapeutic options beyond reperfusion therapy to effectively reduce neurologic deficits. The inflammatory response associated with ischemic stroke involves the complement system proteins. The expression of complement is temporally influenced during distinct phases of ischemic stroke. Complement component 1q (C1q) demonstrates a discernable predictive value in relation to the onset of ischemic stroke, potentially attributable to its regulatory impact on atherosclerosis. Complement system proteins implicated in arterial thrombosis pose a risk of precipitating thromboembolic events. The serum concentrations of C1q, mannose-binding lectin (MBL), complement 3 (C3), and membrane attack complex (MAC) exhibit correlations with the severity of neurologic deficits resulting from ischemic stroke. Elevated levels of MBL, C3, and MAC are indicative of a less favorable prognosis in ischemic stroke cases. Complement plays a role in cerebral ischemia-reperfusion injury and is associated with post-stroke cognitive impairment. Both C3 and complement 5 (C5) exert a dual effect on functional recovery following stroke. Complement 4 (C4) proves to be more clinically informative in evaluating strokes occurring in the context of diabetes. Currently, the majority of foundational experimental studies focus on the treatment of ischemic brain injury through the modulation of complement receptor expression. This article reviews the research on the pathogenesis of ischemic stroke and the evaluation of stroke severity and prognosis in the past five years, in order to provide ideas for the treatment of ischemic stroke from onset to long-term prognosis.

Key words: Complement system proteins, Ischemic stroke, Atherosclerosis, Thrombosis, Neurologic deficits

Xin Tang, Wenhai Zhai, Runting Wang, Shengyu Zhou, Hang Jin. Research progress on the role of complement in ischemic stroke[J]. Chinese Journal of Cerebrovascular Diseases(Electronic Edition), 2024, 18(04): 382-392.

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References 121

1	Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019 [J]. Lancet Neurol, 2021, 20(10): 795-820.
2	Gu X, Li Y, Chen S, et al. Association of lipids with ischemic and hemorrhagic stroke: a prospective cohort study among 267 500 Chinese [J]. Stroke, 2019, 50(12): 3376-3384.
3	Hackam DG. Optimal medical management of asymptomatic carotid stenosis [J]. Stroke, 2021, 52(6): 2191-2198.
4	Gorelick PB, Wong KS, Bae HJ, et al. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier [J]. Stroke, 2008, 39(8): 2396-2399.
5	Björkegren JLM, Lusis AJ. Atherosclerosis: recent developments [J]. Cell, 2022, 185(10): 1630-1645.
6	Tsivgoulis G, Katsanos AH, Sandset EC, et al. Thrombolysis for acute ischaemic stroke: current status and future perspectives [J]. Lancet Neurol, 2023, 22(5): 418-429.
7	Widimsky P, Snyder K, Sulzenko J, et al. Acute ischaemic stroke: recent advances in reperfusion treatment [J]. Eur Heart J, 2023, 44(14): 1205-1215.
8	Zhou Y, He Y, Yan S, et al. Reperfusion injury is associated with poor outcome in patients with recanalization after thrombectomy [J]. Stroke, 2023, 54(1): 96-104.
9	张运, 裴月红, 傅瑜. 急性缺血性卒中静脉溶栓治疗进展 [J/OL]. 中华脑血管病杂志(电子版), 2023, 17(2): 83-88.
10	Ma Y, Liu Y, Zhang Z, et al. Significance of complement system in ischemic stroke: a comprehensive review [J]. Aging Dis, 2019, 10(2): 429-462.
11	Walport MJ. Complement. First of two parts [J]. N Engl J Med, 2001, 344(14): 1058-1066.
12	Walport MJ. Complement. Second of two parts [J]. N Engl J Med, 2001, 344(15): 1140-1144.
13	Coppin L, Sokal E, Stéphenne X. Thrombogenic risk induced by intravascular mesenchymal stem cell therapy: current status and future perspectives [J]. Cells, 2019, 8(10): 1160.
14	Harrison RA. The properdin pathway: an "alternative activation pathway" or a "critical amplification loop" for C3 and C5 activation? [J]. Semin Immunopathol, 2018, 40(1): 15-35.
15	Xie CB, Jane-Wit D, Pober JS. Complement membrane attack complex: new roles, mechanisms of action, and therapeutic targets [J]. Am J Pathol, 2020, 190(6): 1138-1150.
16	Mitaki S, Wada Y, Sheikh AM, et al. Proteomic analysis of extracellular vesicles enriched serum associated with future ischemic stroke [J]. Sci Rep, 2021, 11(1): 24024.
17	Xing Z, Wang Y, Gong K, et al. Plasma C4 level was associated with mortality, cardiovascular and cerebrovascular complications in hemodialysis patients [J]. BMC Nephrol, 2022, 23(1): 232.
18	Zhang ZG, Wang C, Wang J, et al. Prognostic value of mannose-binding lectin: 90-day outcome in patients with acute ischemic stroke [J]. Mol Neurobiol, 2015, 51(1): 230-239.
19	Zheng M, Wang X, Yang J, et al. Changes of complement and oxidative stress parameters in patients with acute cerebral infarction or cerebral hemorrhage and the clinical significance [J]. Exp Ther Med, 2020, 19(1): 703-709.
20	Zhang B, Yang N, Gao C. Is plasma C3 and C4 levels useful in young cerebral ischemic stroke patients? Associations with prognosis at 3 months [J]. J Thromb Thrombolysis, 2015, 39(2): 209-214.
21	Yang P, Zhu Z, Zang Y, et al. Increased serum complement c3 levels are associated with adverse clinical outcomes after ischemic stroke [J]. Stroke, 2021, 52(3): 868-877.
22	Si W, He P, Wang Y, et al. Complement complex C5b-9 levels are associated with the clinical outcomes of acute ischemic stroke and carotid plaque stability [J]. Transl Stroke Res, 2019, 10(3): 279-286.
23	Hu ZP, Wu F, Du YH, et al. Association between serum complement 1q and the associated factors of acute ischemic stroke in patients with type 2 diabetes [J]. Hum Exp Toxicol, 2023, 42: 9603271231188291.
24	Zhang X, Yin J, Shao K, et al. High serum complement component C4 as a unique predictor of unfavorable outcomes in diabetic stroke [J]. Metab Brain Dis, 2021, 36(8): 2313-2322.
25	Neglia L, Oggioni M, Mercurio D, et al. Specific contribution of mannose-binding lectin murine isoforms to brain ischemia/reperfusion injury [J]. Cell Mol Immunol, 2020, 17(3): 218-226.
26	Li L, Dong L, Xiao Z, et al. Integrated analysis of the proteome and transcriptome in a MCAO mouse model revealed the molecular landscape during stroke progression [J]. J Adv Res, 2020, 24: 13-27.
27	Lin Z, Lin H, Li W, et al. Complement component C3 promotes cerebral ischemia/reperfusion injury mediated by TLR2/NFκB activation in diabetic mice [J]. Neurochem Res, 2018, 43(8): 1599-1607.
28	Chen X, Arumugam TV, Cheng YL, et al. Combination therapy with low-dose IVIG and a C1-esterase inhibitor ameliorates brain damage and functional deficits in experimental ischemic stroke [J]. Neuromolecular Med, 2018, 20(1): 63-72.
29	Zhang LY, Pan J, Mamtilahun M, et al. Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion [J]. Theranostics, 2020, 10(1): 74-90.
30	Ahmad S, Pandya C, Kindelin A, et al. C3a receptor antagonist therapy is protective with or without thrombolysis in murine thromboembolic stroke [J]. Br J Pharmacol, 2020, 177(11): 2466-2477.
31	Wang DD, Hou XH, Li HQ, et al. Association of serum complement C1q concentration with severity of neurological impairment and infarct size in patients with acute ischemic stroke [J]. J Stroke Cerebrovasc Dis, 2020, 29(12): 105363.
32	Grossi C, Artusi C, Meroni P, et al. β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke [J]. J Cereb Blood Flow Metab, 2021, 41(8): 2038-2053.
33	Sasaki S, Nishihira K, Yamashita A, et al. Involvement of enhanced expression of classical complement C1q in atherosclerosis progression and plaque instability: C1q as an indicator of clinical outcome [J]. PLoS One, 2022, 17(1): e0262413.
34	Van Dam-Nolen DHK, Truijman MTB, Van Der Kolk AG, et al. Carotid plaque characteristics predict recurrent ischemic stroke and TIA: the PARISK (Plaque At RISK) study [J]. JACC Cardiovasc Imaging, 2022, 15(10): 1715-1726.
35	林雨, 王艳玲. 颈动脉斑块易损性的评估与干预的研究进展 [J/OL]. 中华脑血管病杂志(电子版), 2023, 17(1): 66-69.
36	Niyonzima N, Bakke SS, Gregersen I, et al. Cholesterol crystals use complement to increase NLRP3 signaling pathways in coronary and carotid atherosclerosis [J]. EBioMedicine, 2020, 60: 102985.
37	Yurdagul AJr, Doran AC, Cai B, et al. Mechanisms and consequences of defective efferocytosis in atherosclerosis [J]. Front Cardiovasc Med, 2017, 4: 86.
38	Wicker-Planquart C, Dufour S, Tacnet-Delorme P, et al. Molecular and cellular interactions of scavenger receptor SR-F1 with complement C1q provide insights into its role in the clearance of apoptotic cells [J]. Front Immunol, 2020, 11: 544.
39	Manta CP, Leibing T, Friedrich M, et al. Targeting of scavenger receptors stabilin-1 and stabilin-2 ameliorates atherosclerosis by a plasma proteome switch mediating monocyte/macrophage suppression [J]. Circulation, 2022, 146(23): 1783-1799.
40	Rawish E, Sauter M, Sauter R, et al. Complement, inflammation and thrombosis [J]. Br J Pharmacol, 2021, 178(14): 2892-2904.
41	Sauter RJ, Sauter M, Reis ES, et al. Functional relevance of the anaphylatoxin receptor C3aR for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis [J]. Circulation, 2018, 138(16): 1720-1735.
42	Ahmad S, Kindelin A, Khan SA, et al. C3a receptor inhibition protects brain endothelial cells against oxygen-glucose deprivation/reperfusion [J]. Exp Neurobiol, 2019, 28(2): 216-228.
43	Li Y, Xin G, Li S, et al. PD-L1 regulates platelet activation and thrombosis via caspase-3/GSDME pathway [J]. Front Pharmacol, 2022, 13: 921414.
44	Santos-López J, De La Paz K, Fernández FJ, et al. Structural biology of complement receptors [J]. Front Immunol, 2023, 14: 1239146.
45	Aiello S, Gastoldi S, Galbusera M, et al. C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19 [J]. Blood Adv, 2022, 6(3): 866-881.
46	Cui J, Li H, Chen Z, et al. Thrombo-inflammation and immunological response in ischemic stroke: focusing on platelet-tregs interaction [J]. Front Cell Neurosci, 2022, 16: 955385.
47	Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases [J]. Transl Res, 2020, 220: 1-13.
48	Loh JT, Zhang B, Teo JKH, et al. Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes [J]. Cytotherapy, 2022, 24(7): 711-719.
49	Chen Y, Li X, Lin X, et al. Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis [J]. Thromb J, 2022, 20(1): 24.
50	De Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: a triangular relationship [J]. Cell Mol Immunol, 2019, 16(1): 19-27.
51	Martinod K, Wagner DD. Thrombosis: tangled up in NETs [J]. Blood, 2014, 123(18): 2768-2776.
52	Geddings JE, Mackman N. New players in haemostasis and thrombosis [J]. Thromb Haemost, 2014, 111(4): 570-574.
53	Simats A, García-Berrocoso T, Montaner J. Neuroinflammatory biomarkers: from stroke diagnosis and prognosis to therapy [J]. Biochim Biophys Acta, 2016, 1862(3): 411-424.
54	Freda CT, Yin W, Ghebrehiwet B, et al. Complement component C1q initiates extrinsic coagulation via the receptor for the globular head of C1q in adventitial fibroblasts and vascular smooth muscle cells [J]. Immun Inflamm Dis, 2023, 11(1): e769.
55	Wang M, Zhang Z, Liu D, et al. Soluble adhesion molecules and functional outcome after ischemic stroke: a mendelian randomization study [J]. J Stroke Cerebrovasc Dis, 2023, 32(6): 107136.
56	Wang YC, Li X, Shen Y, et al. PERK (Protein Kinase RNA-Like ER Kinase) branch of the unfolded protein response confers neuroprotection in ischemic stroke by suppressing protein synthesis [J]. Stroke, 2020, 51(5): 1570-1577.
57	Neglia L, Fumagalli S, Orsini F, et al. Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells [J]. J Cereb Blood Flow Metab, 2020, 40(8): 1608-1620.
58	Orsini F, Fumagalli S, Császár E, et al. Mannose-binding lectin drives platelet inflammatory phenotype and vascular damage after cerebral ischemia in mice via IL (interleukin)-1α [J]. Arterioscler Thromb Vasc Biol, 2018, 38(11): 2678-2690.
59	吴斌, 陈清清, 陈巨罗, 等. 补体C1q和肿瘤坏死因子相关蛋白9在缺血性脑卒中患者中的表达及意义 [J]. 中华老年心脑血管病杂志, 2022, 24(1): 59-62.
60	Molnar T, Csuka D, Pusch G, et al. Associations between serum L-arginine and ficolins in the early phase of acute ischemic stroke - a pilot study [J]. J Stroke Cerebrovasc Dis, 2020, 29(8): 104951.
61	Cao L, Cobbs A, Simon RP, et al. Distinct plasma proteomic changes in male and female African American stroke patients [J]. Int J Physiol Pathophysiol Pharmacol, 2019, 11(2): 12-20.
62	Clarke AR, Christophe BR, Khahera A, et al. Therapeutic modulation of the complement cascade in stroke [J]. Front Immunol, 2019, 10: 1723.
63	Torp MK, Ranheim T, Schjalm C, et al. Intracellular complement component 3 attenuated ischemia-reperfusion injury in the isolated buffer-perfused mouse heart and is associated with improved metabolic homeostasis [J]. Front Immunol, 2022, 13: 870811.
64	Klimova N, Fearnow A, Long A, et al. NAD(+) precursor modulates post-ischemic mitochondrial fragmentation and reactive oxygen species generation via SIRT3 dependent mechanisms [J]. Exp Neurol, 2020, 325: 113144.
65	Wang XX, Mao GH, Li QQ, et al. Neuroprotection of NAD(+) and NBP against ischemia/reperfusion brain injury is associated with restoration of sirtuin-regulated metabolic homeostasis [J]. Front Pharmacol, 2023, 14: 1096533.
66	Gong Z, Pan J, Shen Q, et al. Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury [J]. J Neuroinflammation, 2018, 15(1): 242.
67	Wang L, Ren W, Wu Q, et al. NLRP3 inflammasome activation: a therapeutic target for cerebral ischemia-reperfusion injury [J]. Front Mol Neurosci, 2022, 15: 847440.
68	Li J, Tian S, Wang H, et al. Protection of hUC-MSCs against neuronal complement C3a receptor-mediated NLRP3 activation in CUMS-induced mice [J]. Neurosci Lett, 2021, 741: 135485.
69	Dai S, Liu F, Ren M, et al. Complement inhibition targeted to injury specific neoepitopes attenuates atherogenesis in mice [J]. Front Cardiovasc Med, 2021, 8: 731315.
70	Xin Y, Hertle E, Van Der Kallen CJH, et al. C3 and alternative pathway components are associated with an adverse lipoprotein subclass profile: The CODAM study [J]. J Clin Lipidol, 2021, 15(2): 311-319.
71	Garcia-Arguinzonis M, Diaz-Riera E, Peña E, et al. Alternative C3 complement system: lipids and atherosclerosis [J]. Int J Mol Sci, 2021, 22(10): 5122.
72	Alawieh AM, Langley EF, Feng W, et al. Complement-dependent synaptic uptake and cognitive decline after stroke and reperfusion therapy [J]. J Neurosci, 2020, 40(20): 4042-4058.
73	Bhatia K, Kindelin A, Nadeem M, et al. Complement C3a receptor (C3aR) mediates vascular dysfunction, hippocampal pathology, and cognitive impairment in a mouse model of VCID [J]. Transl Stroke Res, 2022, 13(5): 816-829.
74	Wang Y, Wang B, Liu Y, et al. Inhibition of PI3K/Akt/mTOR signaling by NDRG2 contributes to neuronal apoptosis and autophagy in ischemic stroke [J]. J Stroke Cerebrovasc Dis, 2023, 32(3): 106984.
75	Jiang T, Li Y, He S, et al. Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction [J]. EBioMedicine, 2023, 93: 104653.
76	Cao W, Lin J, Xiang W, et al. Physical exercise-induced astrocytic neuroprotection and cognitive improvement through primary cilia and mitogen-activated protein kinases pathway in rats with chronic cerebral hypoperfusion [J]. Front Aging Neurosci, 2022, 14: 866336.
77	King A, Szekely B, Calapkulu E, et al. The increased densities, but different distributions, of both C3 and S100A10 immunopositive astrocyte-like cells in Alzheimer's disease brains suggest possible roles for both A1 and A2 astrocytes in the disease pathogenesis [J]. Brain Sci, 2020, 10(8): 503.
78	Arba F, Giannini A, Piccardi B, et al. Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke [J]. Eur Stroke J, 2019, 4(2): 119-126.
79	Jin W, Zhao J, Yang E, et al. Neuronal STAT3/HIF-1α/PTRF axis-mediated bioenergetic disturbance exacerbates cerebral ischemia-reperfusion injury via PLA2G4A [J]. Theranostics, 2022, 12(7): 3196-3216.
80	Shu J, Fang XH, Li YJ, et al. Microglia-induced autophagic death of neurons via IL-6/STAT3/miR-30d signaling following hypoxia/ischemia [J]. Mol Biol Rep, 2022, 49(8): 7697-7707.
81	Pekna M, Pekny M. The complement system: a powerful modulator and effector of astrocyte function in the healthy and diseased central nervous system [J]. Cells, 2021, 10(7): 1812.
82	Pekna M, Siqin S, De Pablo Y, et al. Astrocyte responses to complement peptide C3a are highly context-dependent [J]. Neurochem Res, 2023, 48(4): 1233-1241.
83	Aswendt M, Wilhelmsson U, Wieters F, et al. Reactive astrocytes prevent maladaptive plasticity after ischemic stroke [J]. Prog Neurobiol, 2022, 209: 102199.
84	Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia [J]. Nature, 2017, 541(7638): 481-487.
85	Stokowska A, Aswendt M, Zucha D, et al. Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity [J]. J Clin Invest, 2023, 133(10): e162253.
86	Zhang FF, Zhang L, Zhao L, et al. The circular RNA Rap1b promotes Hoxa5 transcription by recruiting Kat7 and leading to increased Fam3a expression, which inhibits neuronal apoptosis in acute ischemic stroke [J]. Neural Regen Res, 2023, 18(10): 2237-2245.
87	Gutierrez J, Turan TN, Hoh BL, et al. Intracranial atherosclerotic stenosis: risk factors, diagnosis, and treatment [J]. Lancet Neurol, 2022, 21(4): 355-368.
88	Zhou X, Chen X, Zhang L, et al. Mannose-binding lectin reduces oxidized low-density lipoprotein induced vascular endothelial cells injury by inhibiting LOX1-ox-LDL binding and modulating autophagy [J]. Biomedicines, 2023, 11(6): 1743.
89	Carbone F, Valente A, Perego C, et al. Ficolin-2 serum levels predict the occurrence of acute coronary syndrome in patients with severe carotid artery stenosis [J]. Pharmacol Res, 2021, 166: 105462.
90	Schoeps B, Frädrich J, Krüger A. Cut loose TIMP-1: an emerging cytokine in inflammation [J]. Trends Cell Biol, 2023, 33(5): 413-426.
91	Arjunan A, Sah DK, Woo M, et al. Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome [J]. Cell Biosci, 2023, 13(1): 16.
92	Casado ME, Collado-Pérez R, Frago LM, et al. Recent advances in the knowledge of the mechanisms of leptin physiology and actions in neurological and metabolic pathologies [J]. Int J Mol Sci, 2023, 24(2): 1422.
93	Sotler T, Šebeštjen M. PCSK9 as an atherothrombotic risk factor [J]. Int J Mol Sci, 2023, 24(3): 1966.
94	Barakzie A, Jansen AJG, Ten Cate H, et al. Coagulation biomarkers for ischemic stroke [J]. Res Pract Thromb Haemost, 2023, 7(4): 100160.
95	Eriksson O, Hultström M, Persson B, et al. Mannose-binding lectin is associated with thrombosis and coagulopathy in critically ill COVID-19 patients [J]. Thromb Haemost, 2020, 120(12): 1720-1724.
96	Durigutto P, Macor P, Pozzi N, et al. Complement activation and thrombin generation by MBL bound to β2-glycoprotein I [J]. J Immunol, 2020, 205(5): 1385-1392.
97	Ma YH, Leng XY, Dong Y, et al. Risk factors for intracranial atherosclerosis: a systematic review and meta-analysis [J]. Atherosclerosis, 2019, 281: 71-77.
98	El Khoudary SR, Chen X, Mcconnell D, et al. Associations of HDL subclasses and lipid content with complement proteins over the menopause transition: The SWAN HDL ancillary study: HDL and complement proteins in women [J]. J Clin Lipidol, 2022, 16(5): 649-657.
99	Sereti E, Stamatelopoulos KS, Zakopoulos NA, et al. Hypertension: An immune related disorder? [J]. Clin Immunol, 2020, 212: 108247.
100	Nguyen VA, Riddell N, Crewther SG, et al. Longitudinal stroke recovery associated with dysregulation of complement system-a proteomics pathway analysis [J]. Front Neurol, 2020, 11: 692.
101	Alawieh A, Langley EF, Tomlinson S. Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice [J]. Sci Transl Med, 2018, 10(441): eaao6459.
102	Surugiu R, Catalin B, Dumbrava D, et al. Intracortical administration of the complement C3 receptor antagonist trifluoroacetate modulates microglia reaction after brain injury [J]. Neural Plast, 2019, 2019: 1071036.
103	Alawieh A, Andersen M, Adkins DL, et al. Acute complement inhibition potentiates neurorehabilitation and enhances tPA-mediated neuroprotection [J]. J Neurosci, 2018, 38(29): 6527-6545.
104	Fandaros M, Joseph K, Kaplan AP, et al. gC1qR antibody can modulate endothelial cell permeability in angioedema [J]. Inflammation, 2022, 45(1): 116-128.
105	Delgardo M, Tang AJ, Tudor T, et al. Role of gC1qR as a modulator of endothelial cell permeability and contributor to post-stroke inflammation and edema formation [J]. Front Cell Neurosci, 2023, 17: 1123365.
106	Mercurio D, Piotti A, Valente A, et al. Plasma-derived and recombinant C1 esterase inhibitor: binding profiles and neuroprotective properties in brain ischemia/reperfusion injury [J]. Brain Behav Immun, 2021, 93: 299-311.
107	Shi Y, Jin Y, Li X, et al. C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion [J]. ACS Chem Neurosci, 2021, 12(21): 3994-4006.
108	Kumar P, Hair P, Cunnion K, et al. Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model [J]. PLoS One, 2021, 16(9): e0257960.
109	Wiesmann C, Katschke KJ, Yin J, et al. Structure of C3b in complex with CRIg gives insights into regulation of complement activation [J]. Nature, 2006, 444(7116): 217-220.
110	石艳超, 韩晋, 李强, 等. 补体C5a受体1拮抗剂对小鼠脑缺血/再灌注的保护作用 [J]. 中风与神经疾病杂志, 2022, 39(12): 1082-1085.
111	Grannonico M, Brandolini L, Varrassi G, et al. DF3016A induces increased BDNF transcription in ischemic neuroinflammation injury [J]. Brain Res, 2020, 1748: 147057.
112	Shah TA, Pallera HK, Kaszowski CL, et al. Therapeutic hypothermia inhibits the classical complement pathway in a rat model of neonatal hypoxic-ischemic encephalopathy [J]. Front Neurosci, 2021, 15: 616734.
113	Wang Y, Su Y, Lai W, et al. Salidroside restores an anti-inflammatory endothelial phenotype by selectively inhibiting endothelial complement after oxidative stress [J]. Inflammation, 2020, 43(1): 310-325.
114	Brandolini L, Grannonico M, Bianchini G, et al. The novel C5aR antagonist DF3016A protects neurons against ischemic neuroinflammatory injury [J]. Neurotox Res, 2019, 36(1): 163-174.
115	Liu Y, Wu C, Hou Z, et al. Pseudoginsenoside-F11 accelerates microglial phagocytosis of myelin debris and attenuates cerebral ischemic injury through complement receptor 3 [J]. Neuroscience, 2020, 426: 33-49.
116	Ma Y, Liu Z, Jiang L, et al. Endothelial progenitor cell transplantation attenuates synaptic loss associated with enhancing complement receptor 3-dependent microglial/macrophage phagocytosis in ischemic mice [J]. J Cereb Blood Flow Metab, 2023, 43(3): 379-392.
117	Song S, Guo L, Wu D, et al. Quantitative proteomic analysis of plasma after remote ischemic conditioning in a rhesus monkey ischemic stroke model [J]. Biomolecules, 2021, 11(8): 1164.
118	Ma Y, Jiang L, Wang L, et al. Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice [J]. J Cereb Blood Flow Metab, 2020, 40(12): 2374-2386.
119	Ames RS, Lee D, Foley JJ, et al. Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models [J]. J Immunol, 2001, 166(10): 6341-6348.
120	Li XX, Kumar V, Clark RJ, et al. The "C3aR Antagonist" SB290157 is a partial C5aR2 agonist [J]. Front Pharmacol, 2020, 11: 591398.
121	Lyu Q, Pang X, Zhang Z, et al. Microglial V-set and immunoglobulin domain-containing 4 protects against ischemic stroke in mice by suppressing TLR4-regulated inflammatory response [J]. Biochem Biophys Res Commun, 2020, 522(3): 560-567.

补体种类	主要研究对象	采集时间	较正常范围或对照组	文献
C1q亚组分亚基B和C1r亚组分	参加健康检查的患者	缺血性卒中发作前7.3±4.4年	升高	^[16]
C1q	2型糖尿病患者	AIS发病后48 h内	升高	^[23]
C1q	AIS患者	AIS发病后7 d内	升高	^[31]
MBL	AIS患者	AIS发病后2 d内	升高	^[18]
MBL-A	短暂MCAO小鼠模型	缺血后24 h	升高	^[25]
MBL-C	短暂MCAO小鼠模型	缺血后48 h	升高	^[25]
C4	AIS患者	AIS发病后3~4 d	降低	^[19]
	糖尿病患者	AIS患者入院后第2天	升高	^[24]
	维持性血液透析的患者	血液透析治疗5年时	升高	^[17]
C3	首次AIS患者	AIS发病后2 d内	升高	^[20]
	AIS患者	AIS发病后3 d内	升高	^[21]
	AIS患者	AIS发病后3~4 d	升高	^[19]
	MCAO/R小鼠模型	术后0、6、12和24 h	升高	^[26]
	短暂MCAO糖尿病小鼠模型	缺血1 h后再灌注开始后2、6、12和 24 h	升高	^[27]
	短暂MCAO小鼠模型	缺血再灌注损伤24 h后	升高	^[28]
C3a	二血管阻塞慢性脑缺血大鼠模型	术后7、14、28 d	术后7 d为升高峰值	^[29]
C3a	栓塞性MCAO小鼠模型	术后6 h	升高	^[30]
C3b	短暂MCAO小鼠模型	术后6、24、48、96 h，7 d	术后48 h为升高峰值	^[32]
C3b	短暂MCAO小鼠模型	缺血1 h再灌注72 h后	升高	^[28]
MAC	AIS患者	AIS发病后72 h内	升高	^[22]

补体种类	主要研究对象	采集时间	较正常范围或对照组	文献
C1q亚组分亚基B和C1r亚组分	参加健康检查的患者	缺血性卒中发作前7.3±4.4年	升高	^[16]
C1q	2型糖尿病患者	AIS发病后48 h内	升高	^[23]
C1q	AIS患者	AIS发病后7 d内	升高	^[31]
MBL	AIS患者	AIS发病后2 d内	升高	^[18]
MBL-A	短暂MCAO小鼠模型	缺血后24 h	升高	^[25]
MBL-C	短暂MCAO小鼠模型	缺血后48 h	升高	^[25]
C4	AIS患者	AIS发病后3~4 d	降低	^[19]
	糖尿病患者	AIS患者入院后第2天	升高	^[24]
	维持性血液透析的患者	血液透析治疗5年时	升高	^[17]
C3	首次AIS患者	AIS发病后2 d内	升高	^[20]
	AIS患者	AIS发病后3 d内	升高	^[21]
	AIS患者	AIS发病后3~4 d	升高	^[19]
	MCAO/R小鼠模型	术后0、6、12和24 h	升高	^[26]
	短暂MCAO糖尿病小鼠模型	缺血1 h后再灌注开始后2、6、12和 24 h	升高	^[27]
	短暂MCAO小鼠模型	缺血再灌注损伤24 h后	升高	^[28]
C3a	二血管阻塞慢性脑缺血大鼠模型	术后7、14、28 d	术后7 d为升高峰值	^[29]
C3a	栓塞性MCAO小鼠模型	术后6 h	升高	^[30]
C3b	短暂MCAO小鼠模型	术后6、24、48、96 h，7 d	术后48 h为升高峰值	^[32]
C3b	短暂MCAO小鼠模型	缺血1 h再灌注72 h后	升高	^[28]
MAC	AIS患者	AIS发病后72 h内	升高	^[22]

干预措施	主要作用机制	结局	模型类型	文献
C1INH	抑制补体经典途径、凝集素途径。减少损伤部位C3b沉积，降低Toll样受体2的水平	好转	局灶性脑缺血再灌注小鼠模型	^[28]
重组人C1INH	抑制补体凝集素途径。减少C4b，抑制MBL-A和MBL-C依赖性信号	好转	短暂MCAO/R小鼠模型	^[106]
RLS-0071	抑制补体经典途径。介导局部C1q水平的变化	好转	HIE大鼠模型	^[108]
B4Crry	抑制C3、C3a、C5a和MAC的产生，抑制小胶质细胞活化	好转	小鼠栓塞性卒中后使用t-PA溶栓	^[72]
B4Crry	抑制经典途径和旁路途径。抑制C1q、因子B和C3的表达，促进补体抑制剂CD55和抗凋亡Bcl-2基因的表达，抑制干扰素γ、干扰素调节因子、核因子-κB、STAT3表达，抑制小胶质细胞活化	好转	OGD/R体外模型，MCAO/R小鼠模型	^[101]
治疗性低温	抑制补体经典途径。抑制系统性C1q、C5a的表达，抑制小胶质细胞C1q的表达，减少小胶质细胞和神经元中C3和C9的沉积，抑制凋亡细胞上C1q的结合	好转	HIE大鼠模型	^[112]
内皮祖细胞移植	抑制C3/C3aR通路。抑制星形胶质细胞来源的C3和C3aR表达	好转	短暂MCAO小鼠模型	^[107]
SB290157	减少血管细胞黏附分子1、ICAM-1、E-选择素和P-选择素，减少中性粒细胞黏附	好转	OGD/R体外模型	^[113]
	抑制小胶质细胞活化和小胶质细胞重新分配到髓磷脂	好转	二血管阻塞慢性脑缺血大鼠模型	^[29]
	抑制小胶质细胞的炎症形态变化	好转	MCAO小鼠模型	^[102]
	抑制内皮细胞中ICAM-1、环氧化酶2、还原型辅酶Ⅱ和锰超氧化物歧化酶，抑制ERK的激活，抑制氧化应激，利于恢复内皮细胞的紧密连接	好转	OGD体外模型	^[42]
DF3016A	抑制C5a受体转录，抑制促炎细胞因子过表达，抑制微小RNA-181a过表达	好转	OGD/R体外模型	^[114]
DF3016A	抑制微小RNA-132表达，提高BDNF水平	好转	OGD/R体外模型	^[111]
PMX53	选择性抑制C5a受体，降低肿瘤坏死因子-α、白介素-1β、白介素-6水平，抑制TLR4/NF-κB	好转	MCAO/R大鼠模型，OGD/R体外模型	^[107，110]
CR2fH	抑制补体受体2，抑制补体旁路途径。降低肿瘤坏死因子-α并升高BDNF水平。减少星形胶质细胞瘢痕形成	好转	短暂MCAO小鼠模型	^[103]
CR2fH	抑制补体旁路途径	好转	小鼠栓塞性卒中后使用t-PA溶栓	^[103]
抗CD11b mAb	抑制补体受体3（CR3），削弱小胶质细胞吞噬髓鞘碎片的能力	恶化	体内永久性MCAO模型	^[115]
LA-1	激动CR3，增加突触素和突触后致密蛋白-95的表达	好转	短暂MCAO小鼠模型	^[116]
远隔缺血处理	激活补体经典途径，上调补体 C3、C4b结合蛋白β链亚型X2、补体 C1s 亚组分	好转	MCAO成年恒河猴模型	^[117]

干预措施	主要作用机制	结局	模型类型	文献
C1INH	抑制补体经典途径、凝集素途径。减少损伤部位C3b沉积，降低Toll样受体2的水平	好转	局灶性脑缺血再灌注小鼠模型	^[28]
重组人C1INH	抑制补体凝集素途径。减少C4b，抑制MBL-A和MBL-C依赖性信号	好转	短暂MCAO/R小鼠模型	^[106]
RLS-0071	抑制补体经典途径。介导局部C1q水平的变化	好转	HIE大鼠模型	^[108]
B4Crry	抑制C3、C3a、C5a和MAC的产生，抑制小胶质细胞活化	好转	小鼠栓塞性卒中后使用t-PA溶栓	^[72]
B4Crry	抑制经典途径和旁路途径。抑制C1q、因子B和C3的表达，促进补体抑制剂CD55和抗凋亡Bcl-2基因的表达，抑制干扰素γ、干扰素调节因子、核因子-κB、STAT3表达，抑制小胶质细胞活化	好转	OGD/R体外模型，MCAO/R小鼠模型	^[101]
治疗性低温	抑制补体经典途径。抑制系统性C1q、C5a的表达，抑制小胶质细胞C1q的表达，减少小胶质细胞和神经元中C3和C9的沉积，抑制凋亡细胞上C1q的结合	好转	HIE大鼠模型	^[112]
内皮祖细胞移植	抑制C3/C3aR通路。抑制星形胶质细胞来源的C3和C3aR表达	好转	短暂MCAO小鼠模型	^[107]
SB290157	减少血管细胞黏附分子1、ICAM-1、E-选择素和P-选择素，减少中性粒细胞黏附	好转	OGD/R体外模型	^[113]
	抑制小胶质细胞活化和小胶质细胞重新分配到髓磷脂	好转	二血管阻塞慢性脑缺血大鼠模型	^[29]
	抑制小胶质细胞的炎症形态变化	好转	MCAO小鼠模型	^[102]
	抑制内皮细胞中ICAM-1、环氧化酶2、还原型辅酶Ⅱ和锰超氧化物歧化酶，抑制ERK的激活，抑制氧化应激，利于恢复内皮细胞的紧密连接	好转	OGD体外模型	^[42]
DF3016A	抑制C5a受体转录，抑制促炎细胞因子过表达，抑制微小RNA-181a过表达	好转	OGD/R体外模型	^[114]
DF3016A	抑制微小RNA-132表达，提高BDNF水平	好转	OGD/R体外模型	^[111]
PMX53	选择性抑制C5a受体，降低肿瘤坏死因子-α、白介素-1β、白介素-6水平，抑制TLR4/NF-κB	好转	MCAO/R大鼠模型，OGD/R体外模型	^[107，110]
CR2fH	抑制补体受体2，抑制补体旁路途径。降低肿瘤坏死因子-α并升高BDNF水平。减少星形胶质细胞瘢痕形成	好转	短暂MCAO小鼠模型	^[103]
CR2fH	抑制补体旁路途径	好转	小鼠栓塞性卒中后使用t-PA溶栓	^[103]
抗CD11b mAb	抑制补体受体3（CR3），削弱小胶质细胞吞噬髓鞘碎片的能力	恶化	体内永久性MCAO模型	^[115]
LA-1	激动CR3，增加突触素和突触后致密蛋白-95的表达	好转	短暂MCAO小鼠模型	^[116]
远隔缺血处理	激活补体经典途径，上调补体 C3、C4b结合蛋白β链亚型X2、补体 C1s 亚组分	好转	MCAO成年恒河猴模型	^[117]

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