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Journal of Neuroinflammation

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Open Access 01-12-2012 | Research

Expression of Scavenger receptor A on antigen presenting cells is important for CD4⁺ T-cells proliferation in EAE mouse model

Authors: Hilit Levy-Barazany, Dan Frenkel

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by damage to the neuronal myelin sheath. One of the key effectors for inflammatory injury is the antigen-presenting cell (APC). The class A scavenger receptor (SRA), constitutively expressed by APCs, such as macrophages and dendritic cells in peripheral tissues and the CNS, was shown to play a role in the phagocytosis of myelin; however, the role of SRA in the development of experimental autoimmune encephalomyelitis (EAE) and autoimmune reaction in the periphery has not yet been studied.

Methods

We investigated EAE progression in wild-type (WT) vs. SRA^−/− mice using clinical score measurements and characterized CNS pathology using staining. Furthermore, we assessed SRA role in mediating anti myelin pro-inflammatory response in cell cultures.

Results

We discovered that EAE progression and CNS demyelination were significantly reduced in SRA^−/− mice compared to WT mice. In addition, there was a reduction of infiltrating peripheral immune cells, such as T cells and macrophages, in the CNS lesion of SRA^−/− mice, which was associated with reduced astrogliosis. Immunological assessment showed that SRA deficiency resulted in significant reduction of pro-inflammatory cytokines that play a major role in EAE progression, such as IL-2, IFN-gamma, IL-17 and IL-6. Furthermore, we discovered that SRA^−/− APCs showed impairments in activation and in their ability to induce pro-inflammatory CD4⁺ T cell proliferation.

Conclusion

Expression of SRA on APCs is important for CD4⁺ T-cells proliferation in EAE mouse model. Further studies of SRA-mediated cellular pathways in APCs may offer useful insights into the development of MS and other autoimmune diseases, providing future avenues for therapeutic intervention.

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Hellings N, Raus J, Stinissen P: Insights into the immunopathogenesis of multiple sclerosis. Immunol Res 2002, 25:27–51.CrossRefPubMed

Bhat R, Steinman L: Innate and adaptive autoimmunity directed to the central nervous system. Neuron 2009, 64:123–132.CrossRefPubMed

Frohman EM, Filippi M, Stuve O, Waxman SG, Corboy J, Phillips JT, Lucchinetti C, Wilken J, Karandikar N, Hemmer B, Monson N, De Keyser J, Hartung H, Steinman L, Oksenberg JR, Cree BA, Hauser S, Racke MK: Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions. Arch Neurol 2005, 62:1345–1356.CrossRefPubMed

Lassmann H: The pathology of multiple sclerosis and its evolution. Philos Trans R Soc Lond B Biol Sci 1999, 354:1635–1640.CrossRefPubMedPubMedCentral

Lopez-Diego RS, Weiner HL: Novel therapeutic strategies for multiple sclerosis–a multifaceted adversary. Nat Rev Drug Discov 2008, 7:909–925.CrossRefPubMed

Frohman EM, Stuve O, Havrdova E, Corboy J, Achiron A, Zivadinov R, Sorensen PS, Phillips JT, Weinshenker B, Hawker K, Hartung HP, Steinman L, Zamvil S, Cree BA, Hauser S, Weiner H, Racke MK, Filippi M: Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations. Arch Neurol 2005, 62:1519–1530.PubMed

Yamada Y, Doi T, Hamakubo T, Kodama T: Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system. Cell Mol Life Sci 1998, 54:628–640.CrossRefPubMed

Platt N, Haworth R, Darley L, Gordon S: The many roles of the class A macrophage scavenger receptor. Int Rev Cytol 2002, 212:1–40.CrossRefPubMed

Mukhopadhyay S, Gordon S: The role of scavenger receptors in pathogen recognition and innate immunity. Immunobiology 2004, 209:39–49.CrossRefPubMed

10.

Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010, 140:805–820.CrossRefPubMed

11.

Cotena A, Gordon S, Platt N: The class A macrophage scavenger receptor attenuates CXC chemokine production and the early infiltration of neutrophils in sterile peritonitis. J Immunol 2004, 173:6427–6432.CrossRefPubMed

12.

Tsujita K, Kaikita K, Hayasaki T, Honda T, Kobayashi H, Sakashita N, Suzuki H, Kodama T, Ogawa H, Takeya M: Targeted deletion of class A macrophage scavenger receptor increases the risk of cardiac rupture after experimental myocardial infarction. Circulation 2007, 115:1904–1911.CrossRefPubMed

13.

El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD: Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 1996, 382:716–719.CrossRefPubMed

14.

Frenkel D, Puckett L, Petrovic S, Xia W, Chen G, Vega J, Dembinsky-Vaknin A, Shen J, Plante M, Burt DS, Weiner HL: A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol 2008, 63:591–601.CrossRefPubMedPubMedCentral

15.

Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB: CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 2002, 160:101–112.CrossRefPubMedPubMedCentral

16.

Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM: RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 1996, 382:685–691.CrossRefPubMed

17.

Farfara D, Lifshitz V, Frenkel D: Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease. J Cell Mol Med 2008, 12:762–780.CrossRefPubMedPubMedCentral

18.

Hickman SE, Allison EK, El Khoury J: Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 2008, 28:8354–8360.CrossRefPubMedPubMedCentral

19.

Compston A, Coles A: Multiple sclerosis. Lancet 2002, 359:1221–1231.CrossRefPubMed

20.

Franklin RJ: Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 2002, 3:705–714.CrossRefPubMed

21.

Bruck W, Kuhlmann T, Stadelmann C: Remyelination in multiple sclerosis. J Neurol Sci 2003, 206:181–185.CrossRefPubMed

22.

Gitik M, Reichert F, Rotshenker S: Cytoskeleton plays a dual role of activation and inhibition in myelin and zymosan phagocytosis by microglia. FASEB J 2010, 24:2211–2221.CrossRefPubMed

23.

Reichert F, Rotshenker S: Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages. Neurobiol Dis 2003, 12:65–72.CrossRefPubMed

24.

Smith ME: Phagocytic properties of microglia in vitro: implications for a role in multiple sclerosis and EAE. Microsc Res Tech 2001, 54:81–94.CrossRefPubMed

25.

Levy H, Assaf Y, Frenkel D: Characterization of brain lesions in a mouse model of progressive multiple sclerosis. Exp Neurol 2010, 226:148–158.CrossRefPubMed

26.

Lin W, Kemper A, Dupree JL, Harding HP, Ron D, Popko B: Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain 2006, 129:1306–1318.CrossRefPubMed

27.

Kearn CS: Immunofluorescent mapping of cannibinoid CB1 and dopamine D2 receptors in the mouse brain. LI-COR Biosci 2004,:1–7.

28.

Frenkel D, Pachori AS, Zhang L, Dembinsky-Vaknin A, Farfara D, Petrovic-Stojkovic S, Dzau VJ, Weiner HL: Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury. Int Immunol 2009, 21:817–829.CrossRefPubMedPubMedCentral

29.

O'Connor KC, Bar-Or A, Hafler DA: The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J Clin Immunol 2001, 21:81–92.CrossRefPubMed

30.

Zhu J, Paul WE: Heterogeneity and plasticity of T helper cells. Cell Res 2010, 20:4–12.CrossRefPubMed

31.

Hellings N, Gelin G, Medaer R, Bruckers L, Palmers Y, Raus J, Stinissen P: Longitudinal study of antimyelin T-cell reactivity in relapsing-remitting multiple sclerosis: association with clinical and MRI activity. J Neuroimmunol 2002, 126:143–160.CrossRefPubMed

32.

Weiner HL: A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol 2008,255(Suppl 1):3–11.CrossRefPubMed

33.

Stüve OM, Oksenberg JRP: Multiple Sclerosis Overview. Gene Rev 2006.

34.

Steinman L, Rosenbaum JT, Sriram S, McDevitt HO: In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalitis. Proc Natl Acad Sci U S A 1981, 78:7111–7114.CrossRefPubMedPubMedCentral

35.

Jonker M, van Lambalgen R, Mitchell DJ, Durham SK, Steinman L: Successful treatment of EAE in rhesus monkeys with MHC class II specific monoclonal antibodies. J Autoimmun 1988, 1:399–414.CrossRefPubMed

36.

Nicoletti A, Caligiuri G, Tornberg I, Kodama T, Stemme S, Hansson GK: The macrophage scavenger receptor type A directs modified proteins to antigen presentation. Eur J Immunol 1999, 29:512–521.CrossRefPubMed

37.

Greaves DR, Gordon S: The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. J Lipid Res 2009,50(Suppl):S282–286.PubMedPubMedCentral

38.

Usui HK, Shikata K, Sasaki M, Okada S, Matsuda M, Shikata Y, Ogawa D, Kido Y, Nagase R, Yozai K, Ohga S, Tone A, Wada J, Takeya M, Horiuchi S, Kodama T, Makino H: Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation. Diabetes 2007, 56:363–372.CrossRefPubMed

39.

Hansson GK, Libby P, Schonbeck U, Yan ZQ: Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002, 91:281–291.CrossRefPubMed

40.

Matsumoto A, Naito M, Itakura H, Ikemoto S, Asaoka H, Hayakawa I, Kanamori H, Aburatani H, Takaku F, Suzuki H, et al.: Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions. Proc Natl Acad Sci U S A 1990, 87:9133–9137.CrossRefPubMedPubMedCentral

41.

Hansson GK, Libby P: The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006, 6:508–519.CrossRefPubMed

42.

Haworth R, Platt N, Keshav S, Hughes D, Darley E, Suzuki H, Kurihara Y, Kodama T, Gordon S: The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock. J Exp Med 1997, 186:1431–1439.CrossRefPubMedPubMedCentral

43.

Yi H, Yu X, Gao P, Wang Y, Baek SH, Chen X, Kim HL, Subjeck JR, Wang XY: Pattern recognition scavenger receptor SRA/CD204 down-regulates Toll-like receptor 4 signaling-dependent CD8 T-cell activation. Blood 2009, 113:5819–5828.CrossRefPubMedPubMedCentral

Title: Expression of Scavenger receptor A on antigen presenting cells is important for CD4+ T-cells proliferation in EAE mouse model
Authors: Hilit Levy-Barazany
Dan Frenkel
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-120

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression of Scavenger receptor A on antigen presenting cells is important for CD4⁺ T-cells proliferation in EAE mouse model

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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