Dynamics of major histocompatibility complex class II-positive cells in the postischemic brain - influence of levodopa treatment

Journal of Neuroinflammation

Karsten Ruscher¹  Enida Kuric¹ 

[1]Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, BMC A13, Lund, S-22184, Sweden

关键词: Stroke recovery;    Microglia;    MHC class II;    Levodopa;    Inflammation;    Cytokine;   

Others  :  1151071
DOI  :  10.1186/s12974-014-0145-z

 received in 2014-03-11, accepted in 2014-07-31,  发布年份 2014

【 摘 要 】

Background

Cerebral ischemia activates both the innate and the adaptive immune response, the latter being activated within days after the stroke onset and triggered by the recognition of foreign antigens.

Methods

In this study we have investigated the phenotype of antigen presenting cells and the levels of associated major histocompatibility complex class II (MHC II) molecules in the postischemic brain after transient occlusion of the middle cerebral artery (tMCAO) followed by levodopa/benserazide treatment. Male Sprague Dawley rats were subjected to tMCAO for 105 minutes and received levodopa (20 mg/kg)/benserazide (15 mg/kg) for 5 days starting on day 2 after tMCAO. Thereafter, immune cells were isolated from the ischemic and contralateral hemisphere and analyzed by flow cytometry. Complementarily, the spatiotemporal profile of MHC II-positive (MHC II⁺) cells was studied in the ischemic brain during the first 30 days after tMCAO; protein levels of MHC II and the levels of inflammation associated cytokines were determined in the ischemic hemisphere.

Results

We found that microglia/macrophages represent the main MHC II expressing cell in the postischemic brain one week after tMCAO. No differences in absolute cell numbers were found between levodopa/benserazide and vehicle-treated animals. In contrast, MHC II protein levels were significant downregulated in the ischemic infarct core by levodopa/benserazide treatment. This reduction was accompanied by reduced levels of IFN-γ, TNF-α and IL-4 in the ischemic hemisphere. In the contralateral hemisphere, we exclusively detected MHC II⁺ cells in the corpus callosum. Interestingly, the number of cells was increased by treatment with levodopa/benserazide independent from the infarct size 14 days after tMCAO.

Conclusions

Results suggest that dopamine signaling is involved in the adaptive immune response after stroke and involves microglia/macrophages.

【 授权许可】

   
2014 Kuric and Ruscher.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Lalancette-Hebert M, Phaneuf D, Soucy G, Weng YC, Kriz J: Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation. Brain 2009, 132:940-954.
• [2]Kamel H, Iadecola C: Brain-immune interactions and ischemic stroke: clinical implications. Arch Neurol 2012, 69:576-581.
• [3]Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A: Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 2012, 18:911-917.
• [4]Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996, 19:312-318.
• [5]Morioka T, Kalehua AN, Streit WJ: Characterization of microglial reaction after middle cerebral artery occlusion in rat brain. J Comp Neurol 1993, 327:123-132.
• [6]Smirkin A, Matsumoto H, Takahashi H, Inoue A, Tagawa M, Ohue S, Watanabe H, Yano H, Kumon Y, Ohnishi T, Tanaka J: Iba1 (+)/NG2 (+) macrophage-like cells expressing a variety of neuroprotective factors ameliorate ischemic damage of the brain. J Cereb Blood Flow Metab 2010, 30:603-615.
• [7]Wang LE, Tittgemeyer M, Imperati D, Diekhoff S, Ameli M, Fink GR, Grefkes C: Degeneration of corpus callosum and recovery of motor function after stroke: a multimodal magnetic resonance imaging study. Hum Brain Mapp 2012, 33:2941-2956.
• [8]Fame RM, MacDonald JL, Macklis JD: Development, specification, and diversity of callosal projection neurons. Trends Neurosci 2011, 34:41-50.
• [9]Zhang J, Zhang Y, Xing S, Liang Z, Zeng J: Secondary neurodegeneration in remote regions after focal cerebral infarction: a new target for stroke management? Stroke 2012, 43:1700-1705.
• [10]Smetanka AM, Yee KT, Lund RD: Differential induction of class I and II MHC antigen expression by degenerating myelinated and unmyelinated axons. Brain Res 1990, 521:343-346.
• [11]Planas AM, Gomez-Choco M, Urra X, Gorina R, Caballero M, Chamorro A: Brain-derived antigens in lymphoid tissue of patients with acute stroke. J Immunol 2012, 188:2156-2163.
• [12]Basu S, Dasgupta PS: Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 2000, 102:113-124.
• [13]Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S: The immunoregulatory role of dopamine: an update. Brain Behav Immun 2010, 24:525-528.
• [14]Scheidtmann K, Fries W, Muller F, Koenig E: Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 2001, 358:787-790.
• [15]Acler M, Fiaschi A, Manganotti P: Long-term levodopa administration in chronic stroke patients. A clinical and neurophysiologic single-blind placebo-controlled cross-over pilot study. Restor Neurol Neurosci 2009, 27:277-283.
• [16]Ruscher K, Kuric E, Wieloch T: Levodopa treatment improves functional recovery after experimental stroke. Stroke 2012, 43:507-513.
• [17]Kuric E, Wieloch T, Ruscher K: Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke. Exp Neurol 2013, 247:202-208.
• [18]Kuric E, Ruscher K: Reversal of stroke induced lymphocytopenia by levodopa/benserazide treatment. J Neuroimmunol 2014, 269:94-97.
• [19]Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T: Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 2009, 40:1849-1857.
• [20]Campanella M, Sciorati C, Tarozzo G, Beltramo M: Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 2002, 33:586-592.
• [21]Liesz A, Zhou W, Mracsko E, Karcher S, Bauer H, Schwarting S, Sun L, Bruder D, Stegemann S, Cerwenka A, Sommer C, Dalpke AH, Veltkamp R: Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 2011, 134:704-720.
• [22]Ruscher K, Johannesson E, Brugiere E, Erickson A, Rickhag M, Wieloch T: Enriched environment reduces apolipoprotein E (ApoE) in reactive astrocytes and attenuates inflammation of the peri-infarct tissue after experimental stroke. J Cereb Blood Flow Metab 2009, 29:1796-1805.
• [23]Ruscher K, Kuric E, Liu Y, Walter HL, Issazadeh-Navikas S, Englund E, Wieloch T: Inhibition of CXCL12 signaling attenuates the postischemic immune response and improves functional recovery after stroke. J Cereb Blood Flow Metab 2013, 33:1225-1234.
• [24]Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl U, Meisel A: Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from anin vitromodel.J Neurosci 2002, 22:10291–10301.
• [25]Perry VH: A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J Neuroimmunol 1998, 90:113-121.
• [26]Peng ZC, Kristensson K, Bentivoglio M: Distribution and temporal regulation of the immune response in the rat brain to intracerebroventricular injection of interferon-gamma. Exp Neurol 1998, 154:403-417.
• [27]Panek RB, Benveniste EN: Class II MHC gene expression in microglia. Regulation by the cytokines IFN-gamma, TNF-alpha, and TGF-beta. J Immunol 1995, 154:2846-2854.
• [28]Aspey BS, Taylor FL, Terruli M, Harrison MJ: Temporary middle cerebral artery occlusion in the rat: consistent protocol for a model of stroke and reperfusion. Neuropathol Appl Neurobiol 2000, 26:232-242.
• [29]Markgraf CG, Kraydieh S, Prado R, Watson BD, Dietrich WD, Ginsberg MD: Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague–Dawley and Wistar rats. Stroke 1993, 24:286-292.
• [30]O’Keefe GM, Nguyen VT, Benveniste EN: Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: implications in neurological diseases. J Neurovirol 2002, 8:496-512.
• [31]Felger JC, Abe T, Kaunzner UW, Gottfried-Blackmore A, Gal-Toth J, McEwen BS, Iadecola C, Bulloch K: Brain dendritic cells in ischemic stroke: time course, activation state, and origin. Brain Behav Immun 2010, 24:724-737.
• [32]Hanisch UK: Proteins in microglial activation-inputs and outputs by subsets. Curr Protein Pept Sci 2013, 14:3-15.
• [33]Vass K, Lassmann H: Intrathecal application of interferon gamma. Progressive appearance of MHC antigens within the rat nervous system. Am J Pathol 1990, 137:789-800.
• [34]Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P: DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 2004, 44:269-296.
• [35]Li G, Harton JA, Zhu X, Ting JP: Downregulation of CIITA function by protein kinase a (PKA)-mediated phosphorylation: mechanism of prostaglandin E, cyclic AMP, and PKA inhibition of class II major histocompatibility complex expression in monocytic lines. Mol Cell Biol 2001, 21:4626-4635.
• [36]Ohtaki H, Yin L, Nakamachi T, Dohi K, Kudo Y, Makino R, Shioda S: Expression of tumor necrosis factor alpha in nerve fibers and oligodendrocytes after transient focal ischemia in mice. Neurosci Lett 2004, 368:162-166.
• [37]Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ: Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab 2008, 28:1707-1721.
• [38]Arnett HA, Wang Y, Matsushima GK, Suzuki K, Ting JP: Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J Neurosci 2003, 23:9824-9832.
• [39]Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y: Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 2001, 32:1208-1215.