Skip to main content

Advertisement

SpringerLink
Log in

Modulating the Immune Response Towards a Neuroregenerative Peri-injury Milieu After Cerebral Hemorrhage

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Cerebral hemorrhages account for 15–20 % of stroke sub-types and have very poor prognoses. The mortality rate for cerebral hemorrhage patients is between 40 and 50 %, of which at least half of the deaths occur within the first 2 days, and 75 % of survivors are incapable of living independently after 1 year. Current emergency interventions involve lowering blood pressure and reducing intracranial pressure by controlled ventilations or, in the worst case scenarios, surgical intervention. Some hemostatic and coagulatherapeutic interventions are being investigated, although a few that were promising in experimental studies have failed in clinical trials. No significant immunomodulatory intervention, however, exists for clinical management of cerebral hemorrhage. The inflammatory response following cerebral hemorrhage is particularly harmful in the acute stage because blood–brain barrier disruption is amplified and surrounding tissue is destroyed by secreted proteases and reactive oxygen species from infiltrated leukocytes. In this review, we discuss both the destructive and regenerative roles the immune response play following cerebral hemorrhage and focus on microglia, macrophages, and T-lymphocytes as the primary agents directing the response. Microglia, macrophages, and T-lymphocytes each have sub-types that significantly influence the over-arching immune response towards either a pro-inflammatory, destructive, or an anti-inflammatory, regenerative, state. Both pre-clinical and clinical studies of cerebral hemorrhages that selectively target these immune cells are reviewed and we suggest immunomodulatory therapies that reduce inflammation, while augmenting neural repair, will improve overall cerebral hemorrhage outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Anderson CS et al (2008) Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 7:391–399

    Article  PubMed  Google Scholar 

  • Aronowski J, Hall CE (2005) New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 27:268–279

    Article  PubMed  Google Scholar 

  • Aronowski J, Zhao X (2011) Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke; J Cereb Circ 42:1781–1786

    Article  Google Scholar 

  • Ayer A, Hwang BY, Appelboom G, Connolly ES Jr (2012) Clinical trials for neuroprotective therapies in intracerebral hemorrhage: a new roadmap from bench to bedside. Transl Stroke Res 3:409–417

    Article  PubMed  Google Scholar 

  • Babu R, Bagley JH, Di C, Friedman AH, Adamson C (2012) Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg Focus 32, E8

    Article  PubMed  Google Scholar 

  • Belur PK, Chang JJ, He S, Emanuel BA, Mack WJ (2013) Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury. Neurosurg Focus 34, E9

    Article  PubMed  Google Scholar 

  • Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  CAS  PubMed  Google Scholar 

  • Bogie JF, Stinissen P, Hendriks JJ (2014) Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol 128:191–213

    Article  CAS  PubMed  Google Scholar 

  • Bretscher PA (2014) On the mechanism determining the TH1/TH2 phenotype of an immune response, and its pertinence to strategies for the prevention, and treatment, of certain infectious diseases. Scand J Immunol 79:361–376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brouwers HB, Greenberg SM (2013) Hematoma expansion following acute intracerebral hemorrhage. Cerebrovasc Dis 35:195–201

    Article  PubMed Central  PubMed  Google Scholar 

  • Butcher KS, Jeerakathil T, Hill M, Demchuk AM, Dowlatshahi D, Coutts SB, Gould B, McCourt R, Asdaghi N, Findlay JM, Emery D, Shuaib A, Investigators IA (2013) The intracerebral hemorrhage acutely decreasing arterial pressure trial. Stroke; J Cereb Circ 44:620–626

    Article  Google Scholar 

  • Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen Q, Zhang J, Guo J, Tang J, Tao Y, Li L, Feng H, Chen Z (2014) Chronic hydrocephalus and perihematomal tissue injury developed in a rat model of intracerebral hemorrhage with ventricular extension. Transl Stroke Res

  • Chen S, Yang Q, Chen G, Zhang JH (2015) An update on inflammation in the acute phase of intracerebral hemorrhage. Transl Stroke Res 6:4–8

    Article  PubMed  CAS  Google Scholar 

  • Cheng Y, Xi G, Jin H, Keep RF, Feng J, Hua Y (2014) Thrombin-induced cerebral hemorrhage: role of protease-activated receptor-1. Transl Stroke Res 5:472–475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Chinetti-Gbaguidi G, Colin S, Staels B (2015) Macrophage subsets in atherosclerosis. Nat Rev Cardiol 12:10–17

    Article  CAS  PubMed  Google Scholar 

  • Correale J, Villa A (2004) The neuroprotective role of inflammation in nervous system injuries. J Neurol 251:1304–1316

    Article  PubMed  Google Scholar 

  • Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, Begtrup K, Steiner T, Recombinant Activated Factor VIIIHTI (2006) Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 66:1175–1181

    Article  CAS  PubMed  Google Scholar 

  • Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8:1086–1094

    Article  CAS  PubMed  Google Scholar 

  • Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, Broderick JP (2010) Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke; J Cereb Circ 41:48–53

    Article  CAS  Google Scholar 

  • Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8:337–348

    Article  CAS  PubMed  Google Scholar 

  • Dong C (2011) Genetic controls of Th17 cell differentiation and plasticity. Exp Mol Med 43:1–6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dowlatshahi D, Demchuk AM, Flaherty ML, Ali M, Lyden PL, Smith EE, Collaboration V (2011) Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology 76:1238–1244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ducruet AF, Zacharia BE, Hickman ZL, Grobelny BT, Yeh ML, Sosunov SA, Connolly ES Jr (2009) The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp Neurol 219:398–403

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Eggen BJ, Raj D, Hanisch UK, Boddeke HW (2013) Microglial phenotype and adaptation. J NeuroImmune Pharmacol : Off J Soc NeuroImmune Pharmacol 8:807–823

    Article  CAS  Google Scholar 

  • Fang H, Wang PF, Zhou Y, Wang YC, Yang QW (2013) Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. J Neuroinflammation 10:27

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, O’Garra A (1991) IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol 146:3444–3451

    CAS  PubMed  Google Scholar 

  • Fu Y, Hao J, Zhang N, Ren L, Sun N, Li YJ, Yan Y, Huang D, Yu C, Shi FD (2014) Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol 71:1092–1101

    Article  PubMed  Google Scholar 

  • Gao C, Du H, Hua Y, Keep RF, Strahle J, Xi G (2014a) Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage. J Cereb Blood Flow Metab : Off J Int Soc Cereb Blood Flow Metab 34:1070–1075

    Article  CAS  Google Scholar 

  • Gao L, Lu Q, Huang LJ, Ruan LH, Yang JJ, Huang WL, ZhuGe WS, Zhang YL, Fu B, Jin KL, ZhuGe QC (2014b) Transplanted neural stem cells modulate regulatory T, gammadelta T cells and corresponding cytokines after intracerebral hemorrhage in rats. Int J Mol Sci 15:4431–4441

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Giunti D, Parodi B, Cordano C, Uccelli A, Kerlero de Rosbo N (2014) Can we switch microglia’s phenotype to foster neuroprotection? Focus on multiple sclerosis. Immunology 141:328–339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gonzales NR et al (2013) Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC). Int J Stroke : Off J Int Stroke Soc 8:388–396

    Article  Google Scholar 

  • Gu L, Xiong X, Zhang H, Xu B, Steinberg GK, Zhao H (2012) Distinctive effects of T cell subsets in neuronal injury induced by cocultured splenocytes in vitro and by in vivo stroke in mice. Stroke; J Cereb Circ 43:1941–1946

    Article  CAS  Google Scholar 

  • Guo FQ, Li XJ, Chen LY, Yang H, Dai HY, Wei YS, Huang YL, Yang YS, Sun HB, Xu YC, Yang ZL (2006) Study of relationship between inflammatory response and apoptosis in perihematoma region in patients with intracerebral hemorrhage. Zhongguo wei zhong bing ji jiu yi xue = Chin Crit Care Med = Zhongguo weizhongbing jijiuyixue 18:290–293

    CAS  Google Scholar 

  • Hirota K, Martin B, Veldhoen M (2010) Development, regulation and functional capacities of Th17 cells. Semin Immunopathol 32:3–16

    Article  CAS  PubMed  Google Scholar 

  • Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H (2006) The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. Neurol Sci : Off J Ital Neurol Soc Ital Soc Clin Neurophysiol 27(Suppl 1):S1–7

    Article  Google Scholar 

  • Hosaka K, Hoh BL (2014) Inflammation and cerebral aneurysms. Transl Stroke Res 5:190–198

    Article  CAS  PubMed  Google Scholar 

  • Hua Y, Xi G, Keep RF, Hoff JT (2000) Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg 92:1016–1022

    Article  CAS  PubMed  Google Scholar 

  • Hua Y, Keep RF, Hoff JT, Xi G (2007) Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke; J Cereb Circ 38:759–762

    Article  CAS  Google Scholar 

  • Keep RF, Xi G, Hua Y, Hoff JT (2005) The deleterious or beneficial effects of different agents in intracerebral hemorrhage: think big, think small, or is hematoma size important? Stroke; J Cereb Circ 36:1594–1596

    Article  Google Scholar 

  • Keep RF, Hua Y, Xi G (2012) Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol 11:720–731

    Article  CAS  PubMed  Google Scholar 

  • Klebe D, Krafft PR, Hoffmann C, Lekic T, Flores JJ, Rolland W, Zhang JH (2014) Acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage in neonatal rats. Stroke; J Cereb Circ 45:2475–2479

    Article  CAS  Google Scholar 

  • Kleinewietfeld M, Hafler DA (2013) The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol 25:305–312

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Koga M, Arihiro S, Hasegawa Y, Shiokawa Y, Okada Y, Kimura K, Furui E, Nakagawara J, Yamagami H, Kario K, Okuda S, Tokunaga K, Takizawa H, Takasugi J, Sato S, Nagatsuka K, Minematsu K, Toyoda K, Stroke Acute Management with Urgent Risk-factor A, Improvement Study I (2014) Intravenous nicardipine dosing for blood pressure lowering in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage study. J Stroke Cerebrovasc Dis : Off J National Stroke Assoc 23:2780–2787

    Article  Google Scholar 

  • Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, Blacker D (2013) Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke; J Cereb Circ 44:2493–2499

    Article  CAS  Google Scholar 

  • Kreitzer N, Adeoye O (2013) An update on surgical and medical management strategies for intracerebral hemorrhage. Semin Neurol 33:462–467

    Article  PubMed  Google Scholar 

  • Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26:579–591

    Article  CAS  PubMed  Google Scholar 

  • Lu Q, Gao L, Huang L, Ruan L, Yang J, Huang W, Li Z, Zhang Y, Jin K, Zhuge Q (2014) Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat. J Neuroinflammation 11:44

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4(+)T cells: differentiation and functions. Clin Dev Immunol 2012:925135

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Mantel PY, Schmidt-Weber CB (2011) Transforming growth factor-beta: recent advances on its role in immune tolerance. Methods Mol Biol 677:303–338

    Article  CAS  PubMed  Google Scholar 

  • Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000prime reports 6:13

  • Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci : J Virtual Libr 13:453–461

    Article  CAS  Google Scholar 

  • Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483

    Article  CAS  PubMed  Google Scholar 

  • Mayer SA, Brun NC, Broderick J, Davis SM, Diringer MN, Skolnick BE, Steiner T, United States NovoSeven ICHTI (2006) Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. Neurocrit Care 4:206–214

    Article  CAS  PubMed  Google Scholar 

  • Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T, Investigators FT (2008) Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:2127–2137

    Article  CAS  PubMed  Google Scholar 

  • McCombe PA, Read SJ (2008) Immune and inflammatory responses to stroke: good or bad? Int J Stroke : Off J Int Stroke Soc 3:254–265

    Article  CAS  Google Scholar 

  • Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, Karimi A, Shaw MD, Barer DH, investigators S (2005) Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365:387–397

    Article  PubMed  Google Scholar 

  • Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM, Investigators SI (2013) Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 382:397–408

    Article  PubMed Central  PubMed  Google Scholar 

  • Meng H, Li F, Hu R, Yuan Y, Gong G, Hu S, Feng H (2014) Deferoxamine alleviates chronic hydrocephalus after intraventricular hemorrhage through iron chelation and Wnt1/Wnt3a inhibition. Brain Res

  • Miller CM, Vespa P, Saver JL, Kidwell CS, Carmichael ST, Alger J, Frazee J, Starkman S, Liebeskind D, Nenov V, Elashoff R, Martin N (2008) Image-guided endoscopic evacuation of spontaneous intracerebral hemorrhage. Surg Neurol 69:441–446, discussion 446

    Article  PubMed Central  PubMed  Google Scholar 

  • Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC (1998) Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology 51:1359–1363

    Article  CAS  PubMed  Google Scholar 

  • Morgenstern LB, Hemphill JC, Anderson C 3rd, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messe SR, Mitchell PH, Selim M, Tamargo RJ, American Heart Association Stroke C, Council on Cardiovascular N (2010) Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke; J Cereb Circ 41:2108–2129

    Article  Google Scholar 

  • Mracsko E, Veltkamp R (2014) Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci 8:388

    Article  PubMed Central  PubMed  Google Scholar 

  • Mracsko E, Javidi E, Na SY, Kahn A, Liesz A, Veltkamp R (2014) Leukocyte invasion of the brain after experimental intracerebral hemorrhage in mice. Stroke; J Cereb Circ 45:2107–2114

    Article  Google Scholar 

  • Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nakamura T, Keep RF, Hua Y, Schallert T, Hoff JT, Xi G (2004) Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg 100:672–678

    Article  CAS  PubMed  Google Scholar 

  • Orme J, Mohan C (2012) Macrophage subpopulations in systemic lupus erythematosus. Discov Med 13:151–158

    PubMed  Google Scholar 

  • Pandey AS, Xi G (2014) Intracerebral hemorrhage: a multimodality approach to improving outcome. Transl Stroke Res 5:313–315

    Article  PubMed Central  PubMed  Google Scholar 

  • Peck A, Mellins ED (2010) Plasticity of T-cell phenotype and function: the T helper type 17 example. Immunology 129:147–153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis 71:280–291

    Article  CAS  PubMed  Google Scholar 

  • Qureshi AI, Mendelow AD, Hanley DF (2009) Intracerebral haemorrhage. Lancet 373:1632–1644

    Article  PubMed Central  PubMed  Google Scholar 

  • Rincon F, Friedman DP, Bell R, Mayer SA, Bray PF (2014) Targeted temperature management after intracerebral hemorrhage (TTM-ICH): methodology of a prospective randomized clinical trial. Int J Stroke : Off J Int Stroke Soc 9:646–651

    Article  Google Scholar 

  • Rolland WB 2nd, Manaenko A, Lekic T, Hasegawa Y, Ostrowski R, Tang J, Zhang JH (2011) FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice. Acta Neurochir Suppl 111:213–217

    Article  PubMed Central  PubMed  Google Scholar 

  • Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, Ostrowski R, Manaenko A, Tang J, Zhang JH (2013) Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol 241:45–55

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Romagnani S (1999) Th1/Th2 cells. Inflamm Bowel Dis 5:285–294

    Article  CAS  PubMed  Google Scholar 

  • Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto Y, Koga M, Yamagami H, Okuda S, Okada Y, Kimura K, Shiokawa Y, Nakagawara J, Furui E, Hasegawa Y, Kario K, Arihiro S, Sato S, Kobayashi J, Tanaka E, Nagatsuka K, Minematsu K, Toyoda K, Investigators SS (2013) Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study. Stroke; J Cereb Circ 44:1846–1851

    Article  CAS  Google Scholar 

  • Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K, Geluk A, Ottenhoff TH (2008) Human anti-inflammatory macrophages induce Foxp3+ GITR+ CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol 181:2220–2226

    Article  CAS  PubMed  Google Scholar 

  • Seifert HA, Pennypacker KR (2014) Molecular and cellular immune responses to ischemic brain injury. Transl Stroke Res 5:543–553

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Starke RM, Raper DM, Ding D, Chalouhi N, Owens GK, Hasan DM, Medel R, Dumont AS (2014) Tumor necrosis factor-alpha modulates cerebral aneurysm formation and rupture. Transl Stroke Res 5:269–277

    Article  CAS  PubMed  Google Scholar 

  • Staykov D, Wagner I, Volbers B, Hauer EM, Doerfler A, Schwab S, Bardutzky J (2011) Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke; J Cereb Circ 42:2625–2629

    Article  Google Scholar 

  • Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286

    Article  CAS  PubMed  Google Scholar 

  • Stout RD, Suttles J (2004) Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 76:509–513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J (2005) Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 175:342–349

    Article  CAS  PubMed  Google Scholar 

  • Tapia-Perez H, Sanchez-Aguilar M, Torres-Corzo JG, Rodriguez-Leyva I, Gonzalez-Aguirre D, Gordillo-Moscoso A, Chalita-Williams C (2009) Use of statins for the treatment of spontaneous intracerebral hemorrhage: results of a pilot study. Cent Eur Neurosurg 70:15–20

    Article  CAS  PubMed  Google Scholar 

  • Theodorou GL, Marousi S, Ellul J, Mougiou A, Theodori E, Mouzaki A, Karakantza M (2008) T helper 1 (Th1)/Th2 cytokine expression shift of peripheral blood CD4+ and CD8+ T cells in patients at the post-acute phase of stroke. Clin Exp Immunol 152:456–463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thiex R, Tsirka SE (2007) Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus 22, E6

    Article  PubMed  Google Scholar 

  • van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ (2010) Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 9:167–176

    Article  PubMed  Google Scholar 

  • Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J (2010) Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 92:463–477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab : Off J Int Soc Cereb Blood Flow Metab 27:894–908

    Article  CAS  Google Scholar 

  • Wang WZ, Jiang B, Liu HM, Li D, Lu CZ, Zhao YD, Sander JW (2009) Minimally invasive craniopuncture therapy vs. conservative treatment for spontaneous intracerebral hemorrhage: results from a randomized clinical trial in China. Int J Stroke : Off J Int Stroke Soc 4:11–16

    Article  Google Scholar 

  • Wang N, Liang H, Zen K (2014) Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol 5:614

    PubMed Central  PubMed  Google Scholar 

  • Wee Yong V (2010) Inflammation in neurological disorders: a help or a hindrance? Neuroscientist : Rev J Bringing Neurobiol, Neurol Psychiatry 16:408–420

    Article  CAS  Google Scholar 

  • Wu G, Xi G, Huang F (2006) Spontaneous intracerebral hemorrhage in humans: hematoma enlargement, clot lysis, and brain edema. Acta Neurochir Suppl 96:78–80

    Article  CAS  PubMed  Google Scholar 

  • Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53–63

    Article  PubMed  Google Scholar 

  • Xiong XY, Wang J, Qian ZM, Yang QW (2014) Iron and intracerebral hemorrhage: from mechanism to translation. Transl Stroke Res 5:429–441

    Article  CAS  PubMed  Google Scholar 

  • Xu L, Kitani A, Fuss I, Strober W (2007) Cutting edge: regulatory T cells induce CD4 + CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 178:6725–6729

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Yu A, Liu Y, Shen H, Lin C, Lin L, Wang S, Yuan B (2014) Regulatory T cells inhibit microglia activation and protect against inflammatory injury in intracerebral hemorrhage. Int Immunopharmacol 22:522–525

    Article  CAS  PubMed  Google Scholar 

  • Yoshimura A, Muto G (2011) TGF-beta function in immune suppression. Curr Top Microbiol Immunol 350:127–147

    CAS  PubMed  Google Scholar 

  • Zambrano-Zaragoza JF, Romo-Martinez EJ, Duran-Avelar Mde J, Garcia-Magallanes N, Vibanco-Perez N (2014) Th17 cells in autoimmune and infectious diseases. Int J Inflamm 2014:651503

    Article  Google Scholar 

  • Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, Grotta JC, Aronowski J (2007) Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 61:352–362

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, Grotta J, Gonzales N, Aronowski J (2009) Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke; J Cereb Circ 40:S92–94

    Article  CAS  Google Scholar 

  • Zhao J, Chen Z, Xi G, Keep RF, Hua Y (2014a) Deferoxamine attenuates acute hydrocephalus after traumatic brain injury in rats. Transl Stroke Res 5:586–594

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao X, Sun G, Zhang H, Ting SM, Song S, Gonzales N, Aronowski J (2014b) Polymorphonuclear neutrophil in brain parenchyma after experimental intracerebral hemorrhage. Transl Stroke Res 5:554–561

    Article  PubMed  Google Scholar 

  • Zhou L, Chong MM, Littman DR (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30:646–655

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW (2014) Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol 115:25–44

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Paul WE (2008) CD4 T cells: fates, functions, and faults. Blood 112:1557–1569

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238:247–262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Funding

This review was supported by NIH P01NS082184 to John H. Zhang and Jiping Tang

Conflict of Interest

None.

Author information

Authors and Affiliations

  1. Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    Damon Klebe, Devin McBride, Jerry J. Flores, John H. Zhang & Jiping Tang

  2. Departments of Anesthesiology and Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    John H. Zhang

Authors
  1. Damon Klebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Devin McBride
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerry J. Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John H. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiping Tang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klebe, D., McBride, D., Flores, J.J. et al. Modulating the Immune Response Towards a Neuroregenerative Peri-injury Milieu After Cerebral Hemorrhage. J Neuroimmune Pharmacol 10, 576–586 (2015). https://doi.org/10.1007/s11481-015-9613-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-015-9613-1

Keywords

Search

Navigation