Endotoxin- and ATP-neutralizing activity of alkaline phosphatase as a strategy to limit neuroinflammation

Journal of Neuroinflammation

Jon D Laman¹  Rogier Q Hintzen¹  Ruud Brands³  Joke G Boonstra²  Sabina Onderwater⁴  Karim L Kreft¹  Ruth Huizinga⁴ 

[1] MS Center ErasMS, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;Department of Biochemistry, Alloksys Life Sciences BV, Utrecht, The Netherlands;Department of Immunology, Erasmus MC, University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

关键词: Multiple sclerosis;    Purinergic signalling;    Lipopolysaccharide (LPS);    Neuroimmunology;    Autoimmunity;   

Others  :  1160127
DOI  :  10.1186/1742-2094-9-266

 received in 2012-04-06, accepted in 2012-11-26,  发布年份 2012

【 摘 要 】

Background

Alkaline phosphatase (AP) is a ubiquitously expressed enzyme which can neutralize endotoxin as well as adenosine triphosphate (ATP), an endogenous danger signal released during brain injury. In this study we assessed a potential therapeutic role for AP in inhibiting neuroinflammation using three complementary approaches.

Methods

Mice were immunized to induce experimental autoimmune encephalomyelitis (EAE) and treated with AP for seven days during different phases of disease. In addition, serological assays to determine AP activity, endotoxin levels and endotoxin-reactive antibodies were performed in a cohort of multiple sclerosis (MS) patients and controls. Finally, the expression of AP and related enzymes CD39 and CD73 was investigated in brain tissue from MS patients and control subjects.

Results

AP administration during the priming phase, but not during later stages, of EAE significantly reduced neurological signs. This was accompanied by reduced proliferation of splenocytes to the immunogen, myelin oligodendrocyte glycoprotein peptide. In MS patients, AP activity and isoenzyme distribution were similar to controls. Although endotoxin-reactive IgM was reduced in primary-progressive MS patients, plasma endotoxin levels were not different between groups. Finally, unlike AP and CD73, CD39 was highly upregulated on microglia in white matter lesions of patients with MS.

Conclusions

Our findings demonstrate that: 1) pre-symptomatic AP treatment reduces neurological signs of EAE; 2) MS patients do not have altered circulating levels of AP or endotoxin; and 3) the expression of the AP-like enzyme CD39 is increased on microglia in white matter lesions of MS patients.

【 授权许可】

   
2012 Huizinga et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Perry VH: The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 2004, 18:407-413.
• [2]Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF, van der Meché FG, van Doorn PA, Hintzen RQ: Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002, 125:952-960.
• [3]Correale J, Fiol M, Gilmore W: The risk of relapses in multiple sclerosis during systemic infections. Neurology 2006, 67:652-659.
• [4]Crisi GM, Santambrogio L, Hochwald GM, Smith SR, Carlino JA, Thorbecke GJ: Staphylococcal enterotoxin B and tumor-necrosis factor-alpha-induced relapses of experimental allergic encephalomyelitis: protection by transforming growth factor-beta and interleukin-10. Eur J Immunol 1995, 25:3035-3040.
• [5]Nogai A, Siffrin V, Bonhagen K, Pfueller CF, Hohnstein T, Volkmer-Engert R, Bruck W, Stadelmann C, Kamradt T: Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontransgenic mice via bystander activation of autoreactive CD4+ cells. J Immunol 2005, 175:959-966.
• [6]Mulvey MR, Doupe M, Prout M, Leong C, Hizon R, Grossberndt A, Klowak M, Gupta A, Melanson M, Gomori A, Esfahani F, Klassen L, Frost EE, Namaka M: Staphylococcus aureus harbouring Enterotoxin A as a possible risk factor for multiple sclerosis exacerbations. Mult Scler 2011, 17:397-403.
• [7]Singh AK, Jiang Y: How does peripheral lipopolysaccharide induce gene expression in the brain of rats? Toxicology 2004, 201:197-207.
• [8]Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH: Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005, 25:9275-9284.
• [9]Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, Kasper DL, Kasper LH: Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol 2010, 185:4101-4108.
• [10]Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, Kasper LH: Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 2009, 183:6041-6050.
• [11]Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G: Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011, 479:538-541.
• [12]Poelstra K, Bakker WW, Klok PA, Hardonk MJ, Meijer DK: A physiologic function for alkaline phosphatase: endotoxin detoxification. Lab Invest 1997, 76:319-327.
• [13]Poelstra K, Bakker WW, Klok PA, Kamps JA, Hardonk MJ, Meijer DK: Dephosphorylation of endotoxin by alkaline phosphatase in vivo. Am J Pathol 1997, 151:1163-1169.
• [14]Goldberg RF, Austen WG Jr, Zhang X, Munene G, Mostafa G, Biswas S, McCormack M, Eberlin KR, Nguyen JT, Tatlidede HS, Warren HS, Narisawa S, Millán JL, Hodin RA: Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc Natl Acad Sci U S A 2008, 105:3551-3556.
• [15]Bates JM, Akerlund J, Mittge E, Guillemin K: Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell Host Microbe 2007, 2:371-382.
• [16]Beumer C, Wulferink M, Raaben W, Fiechter D, Brands R, Seinen W: Calf intestinal alkaline phosphatase, a novel therapeutic drug for lipopolysaccharide (LPS)-mediated diseases, attenuates LPS toxicity in mice and piglets. J Pharmacol Exp Ther 2003, 307:737-744.
• [17]Tuin A, Poelstra K, de Jager-Krikken A, Bok L, Raaben W, Velders MP, Dijkstra G: Role of alkaline phosphatase in colitis in man and rats. Gut 2009, 58:379-387.
• [18]Bol-Schoenmakers M, Fiechter D, Raaben W, Hassing I, Bleumink R, Kruijswijk D, Maijoor K, Tersteeg-Zijderveld M, Brands R, Pieters R: Intestinal alkaline phosphatase contributes to the reduction of severe intestinal epithelial damage. Eur J Pharmacol 2010, 633:71-77.
• [19]Chen KT, Malo MS, Moss AK, Zeller S, Johnson P, Ebrahimi F, Mostafa G, Alam SN, Ramasamy S, Warren HS, Hohmann EL, Hodin RA: Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase. Am J Physiol Gastrointest Liver Physiol 2010, 299:G467-G475.
• [20]Trautmann A: Extracellular ATP in the immune system: more than just a “danger signal”. Sci Signal 2009, 2:pe6.
• [21]Khakh BS, North RA: P2X receptors as cell-surface ATP sensors in health and disease. Nature 2006, 442:527-532.
• [22]Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K: ATP drives lamina propria T(H)17 cell differentiation. Nature 2008, 455:808-812.
• [23]Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K: Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007, 110:1225-1232.
• [24]Mills JH, Thompson LF, Mueller C, Waickman AT, Jalkanen S, Niemela J, Airas L, Bynoe MS: CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2008, 105:9325-9330.
• [25]Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS: Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011, 69:292-302.
• [26]Verweij WR, Bentala H, Huizinga-van der Vlag A, van Loenen-Weemaes A, Kooi K, Meijer DK, Poelstra K: Protection against an Escherichia coli-induced sepsis by alkaline phosphatase in mice. Shock 2004, 22:174-179.
• [27]van Veen SQ, Dinant S, van Vliet AK, van Gulik TM: Alkaline phosphatase reduces hepatic and pulmonary injury in liver ischaemia – reperfusion combined with partial resection. Br J Surg 2006, 93:448-456.
• [28]van Veen SQ, van Vliet AK, Wulferink M, Brands R, Boermeester MA, van Gulik TM: Bovine intestinal alkaline phosphatase attenuates the inflammatory response in secondary peritonitis in mice. Infect Immun 2005, 73:4309-4314.
• [29]Su F, Brands R, Wang Z, Verdant C, Bruhn A, Cai Y, Raaben W, Wulferink M, Vincent JL: Beneficial effects of alkaline phosphatase in septic shock. Crit Care Med 2006, 34:2182-2187.
• [30]Zimmermann H: Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 2000, 362:299-309.
• [31]Perry VH, Nicoll JA, Holmes C: Microglia in neurodegenerative disease. Nat Rev Neurol 2010, 6:193-201.
• [32]van der Valk P, Amor S: Preactive lesions in multiple sclerosis. Curr Opin Neurol 2009, 22:207-213.
• [33]Schenk U, Westendorf AM, Radaelli E, Casati A, Ferro M, Fumagalli M, Verderio C, Buer J, Scanziani E, Grassi F: Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci Signal 2008, 1:ra6.
• [34]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8:752-758.
• [35]Matute C, Torre I, Perez-Cerda F, Perez-Samartin A, Alberdi E, Etxebarria E, Arranz AM, Ravid R, Rodriguez-Antiguedad A, Sanchez-Gomez M, Domercq M: P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci 2007, 27:9525-9533.
• [36]Kats S, Brands R, Seinen W, de Jager W, Bekker MW, Hamad MA, Tan ME, Schonberger JP: Anti-inflammatory effects of alkaline phosphatase in coronary artery bypass surgery with cardiopulmonary bypass. Recent Pat Inflamm Allergy Drug Discov 2009, 3:214-220.
• [37]Pickkers P, Heemskerk S, Schouten J, Laterre PF, Vincent JL, Beishuizen A, Jorens PG, Spapen H, Bulitta M, Peters WH, van der Hoeven JG: Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care 2012, 16:R14. BioMed Central Full Text
• [38]Lukas M, Drastich P, Konecny M, Gionchetti P, Urban O, Cantoni F, Bortlik M, Duricova D, Bulitta M: Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis. Inflamm Bowel Dis 2010, 16:1180-1186.
• [39]Ramasamy S, Nguyen DD, Eston MA, Alam SN, Moss AK, Ebrahimi F, Biswas B, Mostafa G, Chen KT, Kaliannan K, Yammine H, Narisawa S, Millán JL, Warren HS, Hohmann EL, Mizoguchi E, Reinecker HC, Bhan AK, Snapper SB, Malo MS, Hodin RA: Intestinal alkaline phosphatase has beneficial effects in mouse models of chronic colitis. Inflamm Bowel Dis 2011, 17:532-542.
• [40]Langer D, Hammer K, Koszalka P, Schrader J, Robson S, Zimmermann H: Distribution of ectonucleotidases in the rodent brain revisited. Cell Tissue Res 2008, 334:199-217.
• [41]Lawrenson JG, Reid AR, Finn TM, Orte C, Allt G: Cerebral and pial microvessels: differential expression of gamma-glutamyl transpeptidase and alkaline phosphatase. Anat Embryol (Berl) 1999, 199:29-34.
• [42]Diaz-Hernandez M, Gomez-Ramos A, Rubio A, Gomez-Villafuertes R, Naranjo JR, Miras-Portugal MT, Avila J: Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 2010, 285:32539-32548.
• [43]Bynoe MS, Viret C: Foxp3+CD4+ T cell-mediated immunosuppression involves extracellular nucleotide catabolism. Trends Immunol 2008, 29:99-102.
• [44]Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, Tubridy N, Mills KH: CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009, 183:7602-7610.
• [45]Schoen SW, Graeber MB, Reddington M, Kreutzberg GW: Light and electron microscopical immunocytochemistry of 5′-nucleotidase in rat cerebellum. Histochemistry 1987, 87:107-113.
• [46]Farber K, Markworth S, Pannasch U, Nolte C, Prinz V, Kronenberg G, Gertz K, Endres M, Bechmann I, Enjyoji K, Robson SC, Kettenmann H: The ectonucleotidase cd39/ENTPDase1 modulates purinergic-mediated microglial migration. Glia 2008, 56:331-341.
• [47]Okada T, Zinchuk VS, Seguchi H: Lipopolysaccharide administration increases acid and alkaline phosphatase reactivity in the cardiac muscle. Microsc Res Tech 2002, 58:421-426.
• [48]Kapojos JJ, Poelstra K, Borghuis T, van den Berg A, Baelde HJ, Klok PA, Bakker WW: Induction of glomerular alkaline phosphatase after challenge with lipopolysaccharide. Int J Exp Pathol 2003, 84:135-144.
• [49]Barclay GR: Endogenous endotoxin-core antibody (EndoCAb) as a marker of endotoxin exposure and a prognostic indicator: a review. Prog Clin Biol Res 1995, 392:263-272.
• [50]Soilu-Hanninen M, Laaksonen M, Laitinen I, Eralinna JP, Lilius EM, Mononen I: A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008, 79:152-157.
• [51]Bennett-Guerrero E, Panah MH, Barclay GR, Bodian CA, Winfree WJ, Andres LA, Reich DL, Mythen MG: Decreased endotoxin immunity is associated with greater mortality and/or prolonged hospitalization after surgery. Anesthesiology 2001, 94:992-998.
• [52]Stephens RC, Fidler K, Wilson P, Barclay GR, Mythen MG, Dixon GL, Turner MW, Klein NJ, Peters MJ: Endotoxin immunity and the development of the systemic inflammatory response syndrome in critically ill children. Intensive Care Med 2006, 32:286-294.
• [53]Gardiner KR, Halliday MI, Barclay GR, Milne L, Brown D, Stephens S, Maxwell RJ, Rowlands BJ: Significance of systemic endotoxaemia in inflammatory bowel disease. Gut 1995, 36:897-901.