Thromb Haemost 2022; 122(09): 1454-1460
DOI: 10.1055/s-0042-1748890
Review Article

Immunity in Stroke: The Next Frontier

Ting Li
1   Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
2   Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China
,
Arthur Liesz
1   Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
3   Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
› Author Affiliations
Funding This study was supported by the European Research Council (ERC-StGs 802305), the National Natural Science Foundation of China (#31600831 and #81771324), and the German Research Foundation (DFG) under Germany's Excellence Strategy (EXC 2145 SyNergy – ID 390857198).

Abstract

Translational stroke research has long been focusing on neuroprotective strategies to prevent secondary tissue injury and promote recovery after acute ischemic brain injury. The inflammatory response to stroke has more recently emerged as a key pathophysiological pathway contributing to stroke outcome. It is now accepted that the inflammatory response is functionally involved in all phases of the ischemic stroke pathophysiology. The immune response is therefore considered a breakthrough target for ischemic stroke treatment. On one side, stroke induces a local neuroinflammatory response, in which the inflammatory activation of glial, endothelial and brain-invading cells contributes to lesion progression after stroke. On the other side, ischemic brain injury perturbs systemic immune homeostasis and results in long-lasting changes of systemic immunity. Here, we briefly summarize current concepts in local neuroinflammation and the systemic immune responses after stroke, and highlight two promising therapeutic strategies for poststroke inflammation.



Publication History

Received: 08 March 2022

Accepted: 16 March 2022

Article published online:
10 June 2022

© 2022. Thieme. All rights reserved.

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Collaborators GS. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18 (05) 439-458
  • 2 Barthels D, Das H. Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol Basis Dis 2020; 1866 (04) 165260
  • 3 Wang W, Jiang B, Sun H. et al; NESS-China Investigators. Prevalence, incidence, and mortality of stroke in China: results from a nationwide population-based survey of 480 687 adults. Circulation 2017; 135 (08) 759-771
  • 4 Hankey GJ. Stroke. Lancet 2017; 389 (10069): 641-654
  • 5 Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ 2020; 368: l6983
  • 6 Powers WJ. Acute ischemic stroke. N Engl J Med 2020; 383 (03) 252-260
  • 7 Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med 2011; 17 (07) 796-808
  • 8 Jian Z, Liu R, Zhu X. et al. The involvement and therapy target of immune cells after ischemic stroke. Front Immunol 2019; 10: 2167
  • 9 Levine SR. Pathophysiology and therapeutic targets for ischemic stroke. Clin Cardiol 2004; 27 (05, Suppl 2): II12-II24
  • 10 De Meyer SF, Denorme F, Langhauser F, Geuss E, Fluri F, Kleinschnitz C. Thromboinflammation in stroke brain damage. Stroke 2016; 47 (04) 1165-1172
  • 11 Stoll G, Nieswandt B. Thrombo-inflammation in acute ischaemic stroke - implications for treatment. Nat Rev Neurol 2019; 15 (08) 473-481
  • 12 Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 2020; 20 (02) 95-112
  • 13 Gelderblom M, Sobey CG, Kleinschnitz C, Magnus T. Danger signals in stroke. Ageing Res Rev 2015; 24 (Pt A): 77-82
  • 14 Shichita T, Ito M, Yoshimura A. Post-ischemic inflammation regulates neural damage and protection. Front Cell Neurosci 2014; 8: 319
  • 15 Wang W, Hu D, Feng Y. et al. Paxillin mediates ATP-induced activation of P2 × 7 receptor and NLRP3 inflammasome. BMC Biol 2020; 18 (01) 182
  • 16 Shichita T, Hasegawa E, Kimura A. et al. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 2012; 18 (06) 911-917
  • 17 Liesz A, Dalpke A, Mracsko E. et al. DAMP signaling is a key pathway inducing immune modulation after brain injury. J Neurosci 2015; 35 (02) 583-598
  • 18 Cockram TOJ, Dundee JM, Popescu AS, Brown GC. The phagocytic code regulating phagocytosis of mammalian cells. Front Immunol 2021; 12: 629979
  • 19 Schulze J, Zierath D, Tanzi P. et al. Severe stroke induces long-lasting alterations of high-mobility group box 1. Stroke 2013; 44 (01) 246-248
  • 20 Nishibori M, Wang D, Ousaka D, Wake H. High mobility group box-1 and blood-brain barrier disruption. Cells 2020; 9 (12) 9
  • 21 Schuhmann MK, Kollikowski AM, März AG, Bieber M, Pham M, Stoll G. Danger-associated molecular patterns are locally released during occlusion in hyper-acute stroke. Brain Behav Immun Health 2021; 15: 100270
  • 22 Ye Y, Zeng Z, Jin T, Zhang H, Xiong X, Gu L. The role of high mobility group box 1 in ischemic stroke. Front Cell Neurosci 2019; 13: 127
  • 23 Kuang X, Wang LF, Yu L. et al. Ligustilide ameliorates neuroinflammation and brain injury in focal cerebral ischemia/reperfusion rats: involvement of inhibition of TLR4/peroxiredoxin 6 signaling. Free Radic Biol Med 2014; 71: 165-175
  • 24 Riddell JR, Wang XY, Minderman H, Gollnick SO. Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4. J Immunol 2010; 184 (02) 1022-1030
  • 25 Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol 2016; 142: 23-44
  • 26 Jia J, Yang L, Chen Y. et al. The role of microglial phagocytosis in ischemic stroke. Front Immunol 2022; 12: 790201
  • 27 Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A. Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders. Expert Opin Ther Targets 2019; 23 (10) 865-882
  • 28 Neher JJ, Emmrich JV, Fricker M, Mander PK, Théry C, Brown GC. Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci U S A 2013; 110 (43) E4098-E4107
  • 29 Jolivel V, Bicker F, Binamé F. et al. Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol 2015; 129 (02) 279-295
  • 30 Xu S, Lu J, Shao A, Zhang JH, Zhang J. Glial cells: role of the immune response in ischemic stroke. Front Immunol 2020; 11: 294
  • 31 Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Prog Neurobiol 2017; 157: 247-272
  • 32 Szalay G, Martinecz B, Lénárt N. et al. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun 2016; 7: 11499
  • 33 Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 2016; 144: 103-120
  • 34 Liddelow SA, Guttenplan KA, Clarke LE. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541 (7638): 481-487
  • 35 Mahmoud S, Gharagozloo M, Simard C, Gris D. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells 2019; 8 (02) E184
  • 36 Shen LH, Li Y, Chopp M. Astrocytic endogenous glial cell derived neurotrophic factor production is enhanced by bone marrow stromal cell transplantation in the ischemic boundary zone after stroke in adult rats. Glia 2010; 58 (09) 1074-1081
  • 37 Guo X, Jiang Q, Tuccitto A. et al. The AMPK-PGC-1α signaling axis regulates the astrocyte glutathione system to protect against oxidative and metabolic injury. Neurobiol Dis 2018; 113: 59-69
  • 38 Min R, van der Knaap MS. Genetic defects disrupting glial ion and water homeostasis in the brain. Brain Pathol 2018; 28 (03) 372-387
  • 39 Langen UH, Ayloo S, Gu C. Development and cell biology of the blood-brain barrier. Annu Rev Cell Dev Biol 2019; 35: 591-613
  • 40 Shan Y, Tan S, Lin Y. et al. The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke. J Neuroinflammation 2019; 16 (01) 242
  • 41 Amantea D, Bagetta G, Tassorelli C, Mercuri NB, Corasaniti MT. Identification of distinct cellular pools of interleukin-1beta during the evolution of the neuroinflammatory response induced by transient middle cerebral artery occlusion in the brain of rat. Brain Res 2010; 1313: 259-269
  • 42 Stanimirovic D, Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol 2000; 10 (01) 113-126
  • 43 Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 2012; 33 (12) 579-589
  • 44 Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol 2007; 184 (1–2): 53-68
  • 45 Ma XJ, Cheng JW, Zhang J. et al. E-selectin deficiency attenuates brain ischemia in mice. CNS Neurosci Ther 2012; 18 (11) 903-908
  • 46 Edwards DN, Salmeron K, Lukins DE, Trout AL, Fraser JF, Bix GJ. Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke. J Cereb Blood Flow Metab 2020; 40 (08) 1695-1708
  • 47 Liesz A, Zhou W, Mracskó É. et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 2011; 134 (Pt 3): 704-720
  • 48 Gelderblom M, Leypoldt F, Steinbach K. et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 2009; 40 (05) 1849-1857
  • 49 Ludewig P, Winneberger J, Magnus T. The cerebral endothelial cell as a key regulator of inflammatory processes in sterile inflammation. J Neuroimmunol 2019; 326: 38-44
  • 50 Wu F, Liu L, Zhou H. Endothelial cell activation in central nervous system inflammation. J Leukoc Biol 2017; 101 (05) 1119-1132
  • 51 Stubbe T, Ebner F, Richter D. et al. Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO. J Cereb Blood Flow Metab 2013; 33 (01) 37-47
  • 52 Chu HX, Kim HA, Lee S. et al. Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia. J Cereb Blood Flow Metab 2014; 34 (03) 450-459
  • 53 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 Neurosci 2014; 34 (50) 16784-16795
  • 54 Filiano AJ, Gadani SP, Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain?. Nat Rev Neurosci 2017; 18 (06) 375-384
  • 55 Gu L, Xiong X, Zhang H, Xu B, Steinberg GK, Zhao H. Distinctive effects of T cell subsets in neuronal injury induced by cocultured splenocytes in vitro and by in vivo stroke in mice. Stroke 2012; 43 (07) 1941-1946
  • 56 Lei TY, Ye YZ, Zhu XQ. et al. The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke. J Neuroinflammation 2021; 18 (01) 25
  • 57 Liesz A, Suri-Payer E, Veltkamp C. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15 (02) 192-199
  • 58 Liesz A, Hu X, Kleinschnitz C, Offner H. Functional role of regulatory lymphocytes in stroke: facts and controversies. Stroke 2015; 46 (05) 1422-1430
  • 59 Shi L, Sun Z, Su W. et al. Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity 2021; 54 (07) 1527.e8-1542.e8
  • 60 Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 2006; 26 (05) 654-665
  • 61 Courties G, Herisson F, Sager HB. et al. Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 2015; 116 (03) 407-417
  • 62 Denes A, McColl BW, Leow-Dyke SF. et al. Experimental stroke-induced changes in the bone marrow reveal complex regulation of leukocyte responses. J Cereb Blood Flow Metab 2011; 31 (04) 1036-1050
  • 63 Haeusler KG, Schmidt WU, Foehring F. et al. Immune responses after acute ischemic stroke or myocardial infarction. Int J Cardiol 2012; 155 (03) 372-377
  • 64 Liu Q, Jin WN, Liu Y. et al. Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations. Immunity 2017; 46 (03) 474-487
  • 65 Shim R, Wong CHY. Complex interplay of multiple biological systems that contribute to post-stroke infections. Brain Behav Immun 2018; 70: 10-20
  • 66 Roth S, Cao J, Singh V. et al. Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade. Immunity 2021; 54 (04) 648-659.e8
  • 67 Boehme AK, McClure LA, Zhang Y. et al. Inflammatory markers and outcomes after lacunar stroke: levels of inflammatory markers in treatment of stroke study. Stroke 2016; 47 (03) 659-667
  • 68 Narasimhalu K, Lee J, Leong YL. et al. Inflammatory markers and their association with post stroke cognitive decline. Int J Stroke 2015; 10 (04) 513-518
  • 69 Kliper E, Bashat DB, Bornstein NM. et al. Cognitive decline after stroke: relation to inflammatory biomarkers and hippocampal volume. Stroke 2013; 44 (05) 1433-1435
  • 70 Li S, Huang Y, Liu Y. et al. Change and predictive ability of circulating immunoregulatory lymphocytes in long-term outcomes of acute ischemic stroke. J Cereb Blood Flow Metab 2021; 41 (09) 2280-2294
  • 71 Neumann J, Riek-Burchardt M, Herz J. et al. Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke. Acta Neuropathol 2015; 129 (02) 259-277
  • 72 Wei Y, Yemisci M, Kim HH. et al. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol 2011; 69 (01) 119-129
  • 73 Qin C, Fan WH, Liu Q. et al. Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway. Stroke 2017; 48 (12) 3336-3346
  • 74 Zhu Z, Fu Y, Tian D. et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 2015; 132 (12) 1104-1112
  • 75 Fu Y, Zhang N, Ren L. et al. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A 2014; 111 (51) 18315-18320
  • 76 Zhang S, Zhou Y, Zhang R. et al. Rationale and design of combination of an immune modulator Fingolimod with Alteplase bridging with Mechanical Thrombectomy in Acute Ischemic Stroke (FAMTAIS) trial. Int J Stroke 2017; 12 (08) 906-909
  • 77 Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA. ASTIN Study Investigators. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke 2003; 34 (11) 2543-2548
  • 78 Amiri-Nikpour MR, Nazarbaghi S, Hamdi-Holasou M, Rezaei Y. An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect. Acta Neurol Scand 2015; 131 (01) 45-50
  • 79 Elkind MSV, Veltkamp R, Montaner J. et al. Natalizumab in acute ischemic stroke (ACTION II): a randomized, placebo-controlled trial. Neurology 2020; 95 (08) e1091-e1104
  • 80 Amarenco P, Lavallée PC, Labreuche J. et al; TIAregistry.org Investigators. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med 2016; 374 (16) 1533-1542
  • 81 Zhang Y, Guan Y, Zhang Y. et al. Recurrence rate and relevant associated factors of stroke among patients with small artery occlusion in Northern China. Sci Rep 2019; 9 (01) 2834
  • 82 Rücker V, Heuschmann PU, O'Flaherty M. et al. Twenty-year time trends in long-term case-fatality and recurrence rates after ischemic stroke stratified by etiology. Stroke 2020; 51 (09) 2778-2785
  • 83 Pennlert J, Eriksson M, Carlberg B, Wiklund PG. Long-term risk and predictors of recurrent stroke beyond the acute phase. Stroke 2014; 45 (06) 1839-1841
  • 84 Amarenco P, Lavallée PC, Monteiro Tavares L. et al; TIAregistry.org Investigators. Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med 2018; 378 (23) 2182-2190
  • 85 Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62 (04) 569-573
  • 86 Kelly PJ, Lemmens R, Tsivgoulis G. Inflammation and stroke risk: a new target for prevention. Stroke 2021; 52 (08) 2697-2706
  • 87 Roth S, Singh V, Tiedt S. et al. Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke. Sci Transl Med 2018; 10 (432) eaao1313
  • 88 Katsanos AH, Palaiodimou L, Price C. et al. Colchicine for stroke prevention in patients with coronary artery disease: a systematic review and meta-analysis. Eur J Neurol 2020; 27 (06) 1035-1038
  • 89 Masson W, Lobo M, Molinero G, Masson G, Lavalle-Cobo A. Role of colchicine in stroke prevention: an updated meta-analysis. J Stroke Cerebrovasc Dis 2020; 29 (05) 104756
  • 90 Stack J, Ryan J, McCarthy G. Colchicine: new insights to an old drug. Am J Ther 2015; 22 (05) e151-e157
  • 91 Leung YY, Yao Hui LL, Kraus VB. Colchicine–Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015; 45 (03) 341-350
  • 92 Kelly P, Weimar C, Lemmens R. et al. Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) - study protocol for a randomised controlled trial. Eur Stroke J 2021; 6 (02) 222-228