缺血性脑卒中免疫炎症反应机制的研究进展

李雪丽; 刘钊; 于博文; 杨鸿

doi:10.16462/j.cnki.zhjbkz.2021.03.019

缺血性脑卒中免疫炎症反应机制的研究进展

doi: 10.16462/j.cnki.zhjbkz.2021.03.019

李雪丽¹,
刘钊¹,
于博文^{1, 2},
杨鸿^1, ,

1.
100700 北京，中国中医科学院医学实验中心，北京市中医药防治重大疾病基础研究重点实验室
2.
100700 北京，中国中医科学院博士后科研流动站

基金项目:

中央级公益性科研院所基本科研业务费专项资金 ZZ2016004

中央级公益性科研院所基本科研业务费专项资金 ZZ13-YQ-081

详细信息

通讯作者:
杨鸿，E-mail: emilia1801@qq.com

中图分类号: R743
计量
- 文章访问数: 1807
- HTML全文浏览量: 408
- PDF下载量: 288
- 被引次数: 0
出版历程
- 收稿日期: 2020-09-03
- 修回日期: 2020-12-04
- 刊出日期: 2021-03-10

Research progress of immune-inflammatory response mechanisms in ischemic stroke

LI Xue-li¹,
LIU Zhao¹,
YU Bo-Wen^{1, 2},
YANG Hong^{1
, ,}

1.
Experimental Research Center, Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, China Academy of Chinese Medical Sciences, Beijing 100700, China
2.
Center for Post-doctoral Studies, China Academy of Chinese Medical Sciences, Beijing 100700, China

Funds:

the Fundamental Research Funds for the Central Public Welfare Research Institutes ZZ2016004

the Fundamental Research Funds for the Central Public Welfare Research Institutes ZZ13-YQ-081

More Information

Corresponding author: YANG Hong, E-mail: emilia1801@qq.com

摘要

摘要: 缺血性脑卒中(ischemic stroke, IS)是世界范围内引起人类死亡、残疾的重大疾病。卒中早期，由死亡和受损神经元释放的多种损伤相关模式分子诱导神经胶质活化、外周免疫应答以及炎性介质分泌增加，从而加速血脑屏障破坏、加剧脑水肿和微循环障碍，造成继发性脑损伤。急性期后，免疫细胞逐渐通过表型改变促进神经元修复，再加上卒中诱导的免疫抑制作用共同影响着卒中的最终结局。本文就炎症反应及免疫应答在缺血性脑卒中发展中的作用机制进行综述，为靶向炎症损伤的缺血性脑卒中辅助治疗药物研发提供参考。
- 缺血性脑卒中 /
- 炎症反应 /
- 免疫应答 /
- 免疫细胞
Abstract: Ischemic stroke is a major disease that causes human death and disability in worldwide. In the early stage of ischemic stroke, danger-/damage-associated molecular patterns (DAMPs) released by injured and dying neurons can induce microglial activation, peripheral immune cell response and increase of inflammatory mediators. This local inflammation leads to the destruction of blood-brain barrier, brain edema and microcirculation disorder, which aggravates secondary brain injury. After the acute phase, various immune cells gradually promote neuronal repairment through phenotypic changes. Combined with stroke induced immunodepression phenomenon, these factors jointly affect the final outcome of stroke. This article reviews the mechanisms of inflammatory response and immune response in the development of ischemic stroke, and provides reference for further researches and development of adjuvant therapy drugs targeting inflammatory injury in ischemic stroke.
- Ischemic stroke /
- Inflammation /
- Immune response /
- Immune cells

HTML全文

参考文献(55)

[1]	Malone K, Amu S, Moore AC, et al. The immune system and stroke: from current targets to future therapy[J]. Immunol Cell Biol, 2019, 97(1): 5-16. DOI: 10.1111/imcb.12191.
[2]	Shi K, Tian DC, Li ZG, et al. Global brain inflammation in stroke[J]. Lancet Neurol, 2019, 18(11): 1058-1066. DOI: 10.1016/S1474-4422(19)30078-X.
[3]	Petrovic-Djergovic D, Goonewardena SN, Pinsky DJ. Inflammatory disequilibrium in stroke[J]. Circ Res, 2016, 119(1): 142-158. DOI: 10.1161/CIRCRESAHA.116.308022.
[4]	Lambertsen KL, Meldgaard M, Ladeby R, et al. A quantitative study of microglial- macrophage synthesis of tumor necrosis factor during acute and late focal cerebral ischemia in mice[J]. J Cereb Blood Flow Metab, 2005, 25(1): 119-135. DOI: 10.1038/sj.jcbfm.9600014.
[5]	Gelderblom M, Leypoldt F, Steinbach K, et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke[J]. Stroke, 2009, 40(5): 1849-1857. DOI: 10.1161/STROKEAHA.108.534503.
[6]	Garaschuk O, Verkhratsky A. Physiology of microglia[J]. Methods Mol Biol, 2019, 2034: 27-40. DOI: 10.1007/978-1-4939-9658-2_3.
[7]	Jickling GC, Liu D, Ander BP, et al. Targeting neutrophils in ischemic stroke: translational insights from experimental studies[J]. J Cereb Blood Flow Metab, 2015, 35(6): 888-901. DOI: 10.1038/jcbfm.2015.45.
[8]	Allen C, Thornton P, Denes A, et al. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA[J]. J Immunol, 2012, 189(1): 381-392. DOI: 10.4049/jimmunol.1200409.
[9]	Hayward NJ, Elliott PJ, Sawyer SD, et al. Lack of evidence for neutrophil participation during infarct formation following focal cerebral ischemia in the rat[J]. Exp Neurol, 1996, 139(2): 188-202. DOI: 10.1006/exnr.1996.0093.
[10]	Breckwoldt MO, Chen JW, Stangenberg L, et al. Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase[J]. Proc Natl Acad Sci, 2008, 105(47): 18584-18589. DOI: 10.1073/pnas.0803945105.
[11]	Kaito M, Araya S, Gondo Y, et al. Relevance of distinct monocyte subsets to clinical course of ischemic stroke patients[J]. PLoS One, 2013, 8(8): e69409. DOI: 10.1371/journal.pone.0069409.
[12]	Gliem M, Mausberg AK, Lee JI, et al. Macrophages prevent hemorrhagic infarct transformation in murine stroke models[J]. Ann Neurol, 2012, 71(6): 743-752. DOI: 10.1002/ana.23529.
[13]	Chu HX, Broughton BR, Kim HA, et al. Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization[J]. Stroke, 2015, 46(7): 1929-1937. DOI: 10.1161/STROKEAHA.115.009426.
[14]	Perego C, Fumagalli S, De Simoni MG. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice[J]. J Neuroinflammation, 2011, 8(1): 174. DOI: 10.1186/1742-2094-8-174.
[15]	Liesz A, Zhou W, Mracskó é, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke[J]. Brain, 2011, 134(Pt3): 704-720. DOI: 10.1093/brain/awr008.
[16]	Ortolano F, Maffia P, Dever G, et al. Advances in imaging of new targets for pharmacological intervention in stroke: real-time tracking of T-cells in the ischaemic brain[J]. Br J Pharmacol, 2010, 159(4): 808-811. DOI: 10.1111/j.1476-5381.2009.00527.x.
[17]	Xie LK, Li WJ, Hersh J, et al. Experimental ischemic stroke induces long-term T cell activation in the brain[J]. J Cereb Blood Flow Metab, 2019, 39(11): 2268-2276. DOI: 10.1177/0271678X18792372.
[18]	Zierath D, Schulze J, Kunze A, et al. The immunologic profile of adoptively transferred lymphocytes influences stroke outcome of recipients[J]. J Neuroimmunol, 2013, 263(1-2): 28-34. DOI: 10.1016/j.jneuroim.2013.07.014.
[19]	Luo Y, Zhou YQ, Xiao W et al. Interleukin-33 ameliorates ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response[J]. Brain Res, 2015, 1597: 86-94. DOI: 10.1016/j.brainres.2014.12.005.
[20]	Grilli M, Barbieri I, Basudev H, et al. Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage[J]. Eur J Neurosci, 2000, 12(7): 2265-2272. DOI: 10.1046/j.1460-9568.2000.00090.x.
[21]	Filiano AJ, Gadani SP, Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain?[J] Nat Rev Neurosci, 2017, 18(6): 375-384. DOI: 10.1038/nrn.2017.39.
[22]	Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke[J]. Nat Med, 2009, 15(2): 192-199. DOI: 10.1038/nm.1927.
[23]	Li PY, Mao LL, Zhou GQ, et al. Adoptive regulatory T-cell therapy preserves systemic immune homeostasis after cerebral ischemia[J]. Stroke, 2013, 44(12): 3509-3515. DOI: 10.1161/STROKEAHA.113.002637.
[24]	Zhao YX, Zhu TR, Li H, et al. Transplantation of lymphocytes co-cultured with human cord blood-derived multipotent stem cells attenuates inflammasome activity in ischemic stroke[J]. Clin Interv Aging, 2019, 14: 2261-2271. DOI: 10.2147/CIA.S223595.
[25]	Li PY, Gan Y, Sun BL, et al. Adoptive regulatory Tcell therapy protects against cerebral ischemia[J]. Ann Neurol, 2013, 74(3): 458-471. DOI: 10.1002/ana.23815.
[26]	Liesz A, Kleinschnitz C. Regulatory T Cells in Post-stroke Immune Homeostasis[J]. Transl Stroke Res, 2016, 7(4): 313-321. DOI: 10.1007/s12975-016-0465-7.
[27]	Kleinschnitz C, Kraft P, Dreykluft A, et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature[J]. Blood, 2013, 121(4): 679-691. DOI: 10.1182/blood-2012-04-426734.
[28]	Mao LL, Li PY, Zhu W et al. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke[J]. Brain, 2017, 140(7): 1914-1931. DOI: 10.1093/brain/awx111.
[29]	Shichita T, Sugiyama Y, Ooboshi H, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury[J]. Nat Med, 2009, 15(8): 946-950. DOI: 10.1038/nm.1999.
[30]	Gelderblom M, Weymar A, Bernreuther C, et al. Neutralization of the IL-17 axis diminishes neutrophil Invasion and protects from ischemic stroke[J]. Blood, 2012, 120(18): 3793-3802. DOI: 10.1182/blood-2012-02-412726.
[31]	Gelderblom M, Arunachalam P, Magnus T. γδ T cells as early sensors of tissue damage and mediators of secondary neurodegeneration[J]. Front Cell Neurosci, 2014, 8: 368. DOI: 10.3389/fncel.2014.00368.
[32]	Mracsko E, Liesz A, Stojanovic A, et al. Antigen dependently activated cluster of differentiation 8-positive T cells cause perforin-mediated neurotoxicity in experimental stroke[J]. J Neurosci, 2014, 34(50): 16784-16795. DOI: 10.1523/JNEUROSCI.1867-14.2014.
[33]	Fan LZ, Zhang CJ, Zhu LW, et al. FasL-PDPK1 pathway promotes the cytotoxicity of CD8⁺ T cells during ischemic stroke[J]. Transl Stroke Res, 2020, 11(4): 747-761. DOI: 10.1007/s12975-019-00749-0.
[34]	Schwab JM, Nguyen TD, Meyermann R, et al. Human focal cerebral infarctions induce differential lesional interleukin-16 (IL-16) expression confined to infiltrating granulocytes, CD8⁺ T-lymphocytes and activated microglia/macrophages[J]. J Neuroimmunol, 2001, 114(1-2): 232-241. DOI: 10.1016/s0165-5728(00)00433-1.
[35]	Zhou YX, Wang X, Tang D, et al. IL-2mAb reduces demyelination after focal cerebral ischemia by suppressing CD8⁺ T cells[J]. CNS Neurosci Ther, 2019, 25(4): 532-543. DOI: 10.1111/cns.13084.
[36]	Selvaraj UM, Poinsatte K, Torres V, et al. Heterogeneity of B Cell Functions in Stroke-Related Risk, Prevention, Injury, and Repair[J]. Neurotherapeutics, 2016, 13(4): 729-747. DOI: 10.1007/s13311-016-0460-4.
[37]	Doyle KP, Quach LN, Solé M, et al. B-lymphocyte-mediated delayed cognitive impairment following stroke[J]. J Neurosci, 2015, 35(5): 2133-2145. DOI: 10.1523/JNEUROSCI.4098-14.2015.
[38]	Yilmaz G, Arumugam TV, Stokes KY, et al. Role of T lymphocytes and interferon-gamma in ischemic stroke[J]. Circulation, 2006, 113(17): 2105-2112. DOI: 10.1161/CIRCULATIONAHA.105.593046.
[39]	Offner H, Hurn PD. A novel hypothesis: regulatory B lymphocytes shape outcome from experimental stroke[J]. Transl Stroke Res, 2012, 3(3): 324-330. DOI: 10.1007/s12975-012-0187-4.
[40]	Yamashiro K, Tanaka R, Urabe T, et al. Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke[J]. PLOS One, 2017, 12(2): e0171521. DOI: 10.1371/journal.pone.0171521.
[41]	Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells[J]. Nat Med, 2016, 22(5): 516-523. DOI: 10.1038/nm.4068.
[42]	Singh V, Roth S, Llovera G, et al. Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke[J]. J Neurosci, 2016, 36(28): 7428-7240. DOI: 10.1523/JNEUROSCI.1114-16.2016.
[43]	Hug A, Dalpke A, Wieczorek N, et al. Infarct volume is a major determiner of post-stroke immune cell function and susceptibility to infection[J]. Stroke, 2009, 40(10): 3226-3232. DOI: 10.1161/STROKEAHA.109.557967.
[44]	Winklewski PJ, Radkowski M, Demkow U. Cross-talk between the inflammatory response, sympathetic activation and pulmonary infection in the ischemic stroke[J]. J Neuroinflammation, 2014, 11: 213. DOI: 10.1186/s12974-014-0213-4.
[45]	Dorrance AM, Fink G. Effects of stroke on the autonomic nervous system[J]. Compr Psychol, 2015, 5(3): 1241-1263. DOI: 10.1002/cphy.c140016.
[46]	Radak D, Resanovic I, Isenovic ER. Changes in hypothalamus-pituitaryadrenal axis following transient ischemic attack[J]. Angiology, 2014, 65(8): 723-732. DOI: 10.1177/0003319713503487.
[47]	Wang H, Deng QW, Peng AN, et al. β-arrestin2 functions as a key regulator in the sympathetic-triggered immunodepression after stroke[J]. Journal of neuroinflammation, 2018, 15(1): 102. DOI: 10.1186/s12974-018-1142-4.
[48]	Zuo L, Shi LH, Yan FL. The reciprocal interaction of sympathetic nervous system and cAMP-PKA-NF-κB pathway in immune suppression after experimental stroke[J]. Neurosci Lett, 2016, 627: 205-210. DOI: 10.1016/j.neulet.2016.05.066.
[49]	Walter U, Kolbaske S, Patejdl R, et al. Insular stroke is associated with acute sympathetic hyperactivation and immunodepression[J]. Eur J Neurol, 2013, 20(1): 153-159. DOI: 10.1111/j.1468-1331.2012.03818.x.
[50]	Cai PY, Bodhit A, Derequito R, et al. Vagus nerve stimulation in ischemic stroke: old wine in a new bottle[J]. Front Neurol, 2014, 5: 107. DOI: 10.3389/fneur.2014.00107.
[51]	Mracsko E, Liesz A, Karcher S, et al. Differential effects of sympathetic nervous system and hypothalamic- pituitary-adrenal axis on systemic immune cells after severe experimental stroke[J]. Brain Behav Immun, 2014, 41: 200-209. DOI: 10.1016/j.bbi.2014.05.015.
[52]	Liu Q, Jin WN, Liu YO, et al. Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations[J]. Immunity, 2017, 46(3): 474-487. DOI: 10.1016/j.immuni.2017.02.015.
[53]	Shi K, Wood K, Shi FD. Stroke-induced immunosuppression and poststroke infection[J]. Stroke and vascular neurology, 2018, 3(1): 34-41. DOI: 10.1136/svn-2017-000123.
[54]	Dasgupta M, Brymer C. Prognosis of delirium in hospitalized elderly: worse than we thought[J]. Int J Geriatr Psychiatry, 2014, 29(5): 497-505. DOI: 10.1002/gps.4032.
[55]	Pendlebury ST, Rothwell PM. Incidence and prevalence of dementia associated with transient ischaemic attack and stroke: analysis of the population-based Oxford Vascular Study[J]. Lancet Neurol, 2019, 18(3): 248-258. DOI: 10.1016/S1474-4422(18)30442-3.