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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2016

Open Access 01-12-2016 | Research article

IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier

Authors: Min Jung Lee, So Jin Bing, Jonghee Choi, Minhee Jang, Gihyun Lee, Hyunkyoung Lee, Byung Soo Chang, Youngheun Jee, Sung Joong Lee, Ik-Hyun Cho

Published in: Molecular Neurodegeneration | Issue 1/2016

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Abstract

Background

The inflammatory myeloid cell activation is one of the hallmarks of experimental autoimmune encephalomyelitis (EAE), yet the in vivo role of the inflammatory myeloid cell activation in EAE has not been clearly resolved. It is well-known that IKK/NF-κB is a key signaling pathway that regulates inflammatory myeloid activation.

Methods

We investigated the in vivo role of inflammatory myeloid cell activation in myelin oligodendrocyte glycoprotein (MOG) peptides-induced EAE using myeloid cell type-specific ikkβ gene conditional knockout-mice (LysM-Cre/Ikkβ F/F ).

Results

In our study, LysM-Cre/Ikkβ F/F mice had alleviated clinical signs of EAE corresponding to the decreased spinal demyelination, microglial activation, and immune cell infiltration in the spinal cord, compared to the wild-type mice (WT, Ikkβ F/F ). Myeloid ikkβ gene deletion significantly reduced the percentage of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells but increased the percentages of CD4+/CD25+/Foxp3+ (Treg) cells in the spinal cord and lymph nodes, corresponding to the altered mRNA expression of IFN-γ, IL-17, IL-23, and Foxp3 in the spinal cords of LysM-Cre/Ikkβ F/F EAE mice. Also, the beneficial effect of myeloid IKKβ deletion in EAE corresponded to the decreased permeability of the blood brain barrier (BBB).

Conclusions

Our findings strongly suggest that IKK/NF-kB-induced myeloid cell activation exacerbates EAE by activating Th1 and Th17 responses and compromising the BBB. The development of NF-κB inhibitory agents with high efficacy through specific targeting of IKKβ in myeloid cells might be of therapeutic potential in MS and other autoimmune disorders.
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Literature
1.
Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta. 2011;1812:252–64.CrossRefPubMed
2.
Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004;55:458–68.CrossRefPubMed
3.
Brambilla R, Dvoriantchikova G, Barakat D, Ivanov D, Bethea JR, Shestopalov VI. Transgenic inhibition of astroglial NF-kappaB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis. J Neuroinflammation. 2012;9:213.CrossRefPubMedPubMedCentral
4.
Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, Ivanov D, Nathanson L, Barnum SR, Bethea JR. Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol. 2009;182:2628–40.CrossRefPubMedPubMedCentral
5.
Brustle A, Brenner D, Knobbe CB, Lang PA, Virtanen C, Hershenfield BM, Reardon C, Lacher SM, Ruland J, Ohashi PS, Mak TW. The NF-kappaB regulator MALT1 determines the encephalitogenic potential of Th17 cells. J Clin Invest. 2012;122:4698–709.CrossRefPubMedPubMedCentral
6.
Bullard DC, Hu X, Adams JE, Schoeb TR, Barnum SR. p150/95 (CD11c/CD18) expression is required for the development of experimental autoimmune encephalomyelitis. Am J Pathol. 2007;170(6):2001–8.CrossRefPubMedPubMedCentral
7.
Chen SJ, Wang YL, Fan HC, Lo WT, Wang CC, Sytwu HK. Current status of the immunomodulation and immunomediated therapeutic strategies for multiple sclerosis. Clin Dev Immunol. 2012;2012:970789.
8.
Chen X, Oppenheim JJ, Winkler-Pickett RT, Ortaldo JR, Howard OM. Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3(+)CD4(+)CD25(+) T regulatory cells in vivo and enhances their capacity to suppress EAE. Eur J Immunol. 2006;36:2139–49.CrossRefPubMed
9.
Cho IH, Hong J, Suh EC, Kim JH, Lee H, Lee JE, Lee S, Kim CH, Kim DW, Jo EK, Lee KE, Karin M, Lee SJ. Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death. Brain. 2008;131:3019–33.CrossRefPubMedPubMedCentral
10.
Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8:265–77.CrossRefPubMed
11.
Dasgupta S, Jana M, Zhou Y, Fung YK, Ghosh S, Pahan K. Antineuroinflammatory effect of NF-kappaB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis. J Immunol. 2004;173:1344–54.CrossRefPubMed
12.
El-behi M, Rostami A, Ciric B. Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2010;5:189–97.CrossRefPubMedPubMedCentral
13.
Ellrichmann G, Thone J, Lee DH, Rupec RA, Gold R, Linker RA. Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation. J Neuroinflammation. 2012;9:15.CrossRefPubMedPubMedCentral
14.
Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol. 2012;33:579–89.CrossRefPubMed
15.
Flynn KM, Michaud M, Canosa S, Madri JA. CD44 regulates vascular endothelial barrier integrity via a PECAM-1 dependent mechanism. Angiogenesis. 2013a;6:689–705.
16.
Flynn KM, Michaud M, Madri JA. CD44 deficiency contributes to enhanced experimental autoimmune encephalomyelitis: a role in immune cells and vascular cells of the blood–brain barrier. Am J Pathol. 2013b;182:1322–36.
17.
Ford AL, Foulcher E, Lemckert FA, Sedgwick JD. Microglia induce CD4 T lymphocyte final effector function and death. J Exp Med. 1996;184(5):1737–45.CrossRefPubMed
18.
Greten FR, Karin M. The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett. 2004;206:193–9.CrossRefPubMed
19.
Greve B, Weissert R, Hamdi N, Bettelli E, Sobel RA, Coyle A, Kuchroo VK, Rajewsky K, Schmidt-Supprian M. I kappa B kinase 2/beta deficiency controls expansion of autoreactive T cells and suppresses experimental autoimmune encephalomyelitis. J Immuno. 2007;179:179–85.
20.
Hendriks JJ, Teunissen CE, de Vries HE, Dijkstra CD. Macrophages and neurodegeneration. Brain Res. 2005;48:185–95.CrossRef
21.
Hilliard B, Samoilova EB, Liu TS, Rostami A, Chen Y. Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells. J Immunol. 1999;163:2937–43.PubMed
22.
Hohlfeld R. Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain. 1997;120(Pt 5):865–916.CrossRefPubMed
23.
Hong J, Cho IH, Kwak KI, Suh EC, Seo J, Min HJ, Choi SY, Kim CH, Park SH, Jo EK, Lee S, Lee KE, Lee SJ. Microglial Toll-like receptor 2 contributes to kainic acid-induced glial activation and hippocampal neuronal cell death. J Biol Chem. 2011;285:39447–57.CrossRef
24.
Hwang I, Ha D, Ahn G, Park E, Joo H, Jee Y. Experimental autoimmune encephalomyelitis: association with mutual regulation of RelA (p65)/NF-kappaB and phospho-IkappaB in the CNS. Biochem Biophys Res Commun. 2011;411:464–70.CrossRefPubMed
25.
Jang M, Cho IH. Sulforaphane Ameliorates 3-Nitropropionic Acid-Induced Striatal Toxicity by Activating the Keap1-Nrf2-ARE Pathway and Inhibiting the MAPKs and NF-kappaB Pathways. Mol Neurobiol. 2016;53(4):2619–35.CrossRefPubMed
26.
Jang M, Lee MJ, Cho IH. Ethyl pyruvate ameliorates 3-nitropropionic acid-induced striatal toxicity through anti-neuronal cell death and anti-inflammatory mechanisms. Brain Behav Immun. 2014;38:151–65.CrossRefPubMed
27.
Kalinowska A, Losy J. PECAM-1, a key player in neuroinflammation. Eur J Neurol. 2006;13(12):1284–90.CrossRefPubMed
28.
Karin M. The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J Biol Chem. 1999;274:27339–42.CrossRefPubMed
29.
Kim H, Ahn M, Choi S, Kim M, Sim KB, Kim J, Moon C, Shin T. Potential role of fibronectin in microglia/macrophage activation following cryoinjury in the rat brain: an immunohistochemical study. Brain Res. 2013;1502:11–9.CrossRefPubMed
30.
Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature. 2012;490(7419)187–91.CrossRefPubMedPubMedCentral
31.
Lassmann H, van Horssen J. The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett. 2011;585:3715–23.CrossRefPubMed
32.
Lee DH, Kubera K, Rosenthal B, Kaltschmidt B, Kaltschmidt C, Gold R, Linker RA. Neuronal NF-kappaB ablation does not influence neuro-axonal degeneration in experimental autoimmune demyelination. J Neuroimmunol. 2012;246:38–42.CrossRefPubMed
33.
Lee MJ, Jang M, Choi J, Chang BS, Kim DY, Kim SH, Kwak YS, Oh S, Lee JH, Chang BJ, Nah SY, Cho IH. Korean red ginseng and ginsenoside-Rb1/-Rg1 alleviates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 T cells and upregulating regulatory T cells. Mol Neurobiol. 2016;53(3):1977–2002.CrossRefPubMed
34.
Lee MJ, Jang M, Choi J, Lee G, Min HJ, Chung WS, Kim JI, Jee Y, Chae Y, Kim SH, Lee SJ, Cho IH. Bee Venom Acupuncture Alleviates Experimental Autoimmune Encephalomyelitis by Upregulating Regulatory T Cells and Suppressing Th1 and Th17 Responses. Mol Neurobiol. 2016;53(3):1419–45.CrossRefPubMed
35.
Linthicum DS. Development of acute autoimmune encephalomyelitis in mice: factors regulating the effector phase of the disease. Immunobiology. 1982;162(3):211–20.CrossRefPubMed
36.
Li X, Li TT, Zhang XH, Hou LF, Yang XQ, Zhu FH, Tang W, Zuo JP. Artemisinin analogue SM934 ameliorates murine experimental autoimmune encephalomyelitis through enhancing the expansion and functions of regulatory T cell. PLoS One. 2013;8:e74108.CrossRefPubMedPubMedCentral
37.
Li ZW, Omori SA, Labuda T, Karin M, Rickert RC. IKK beta is required for peripheral B cell survival and proliferation. J Immunol. 2003;170:4630–7.CrossRefPubMed
38.
Liu YM, Liu XJ, Bai SS, Mu LL, Kong QF, Sun B, Wang DD, Wang JH, Shu S, Wang GY, Li HL. The effect of electroacupuncture on T cell responses in rats with experimental autoimmune encephalitis. J Neuroimmunol. 2010;220:25–33.CrossRefPubMed
39.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001;25:402–8.CrossRefPubMed
40.
Lu G, Zhang R, Geng S, Peng L, Jayaraman P, Chen C, Xu F, Yang J, Li Q, Zheng H, Shen K, Wang J, Liu X, Wang W, Zheng Z, Qi CF, Si C, He JC, Liu K, Lira SA, Sikora AG, Li L, Xiong H. Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun. 2015;6:6676.CrossRefPubMedPubMedCentral
41.
Mc Guire C, Prinz M, Beyaert R, van Loo G. Nuclear factor kappa B (NF-kappaB) in multiple sclerosis pathology. Trends Mol Med. 2013;19:604–13.CrossRefPubMed
42.
McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol. 2007;8:913–9.CrossRefPubMed
43.
Mildner A, Mack M, Schmidt H, Brück W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M. CCR2 + Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain. 2009;132(Pt 9):2487–500.CrossRefPubMed
44.
Miron VE. Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013;16:1211–8.CrossRefPubMedPubMedCentral
45.
Muzio L, Cavasinni F, Marinaro C, Bergamaschi A, Bergami A, Porcheri C, Cerri F, Dina G, Quattrini A, Cxcl10 enhances blood cells migration in the sub-ventricular zone of mice affected by experimental autoimmune encephalomyelitis. Mol Cell Neurosci. 2010;43(3):268–80.
46.
Nam Y, Kim JH, Seo M, Kim JH, Jin M, Jeon S, et al. Lipocalin-2 protein deficiency ameliorates experimental autoimmune encephalomyelitis: the pathogenic role of lipocalin-2 in the central nervous system and peripheral lymphoid tissues. J Biol Chem. 2014;289(24):16773–89.CrossRefPubMedPubMedCentral
47.
Napoli I, Neumann H. Protective effects of microglia in multiple sclerosis. Exp Neurol. 2010;225:24–8.CrossRefPubMed
48.
Nataf S. Neuroinflammation responses and neurodegeneration in multiple sclerosis. Rev Neurol. 2009;165:1023–8.CrossRefPubMed
49.
Nickols JC, Valentine W, Kanwal S, Carter BD. Activation of the transcription factor NF-kappaB in Schwann cells is required for peripheral myelin formation. Nat Neurosci. 2003;6:161–7.CrossRefPubMed
50.
Okamoto K, Iwai Y, Oh-Hora M, Yamamoto M, Morio T, Aoki K, Ohya K, Jetten AM, Akira S, Muta T, Takayanagi H. IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors. Nature. 2010;464:1381–5.CrossRefPubMed
51.
Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, Flores-Alvarado LJ, Mireles-Ramirez MA, Gonzalez-Renovato ED, et al. Role of the Blood–brain Barrier in Multiple Sclerosis. Arch Med Res. 2014;45:687–97.CrossRefPubMed
52.
Pfeiffer F, Schafer J, Lyck R, Makrides V, Brunner S, Schaeren-Wiemers N, Deutsch U, Engelhardt B. Claudin-1 induced sealing of blood–brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis. Acta Neuropathol. 2011;122(5):601–14.CrossRefPubMedPubMedCentral
53.
Reddy J, Illes Z, Zhang X, Encinas J, Pyrdol J, Nicholson L, Sobel RA, Wucherpfennig KW, Kuchroo VK. Myelin proteolipid protein-specific CD4 + CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2004;101:15434–9.CrossRefPubMedPubMedCentral
54.
Sedgwick JD, Schwender S, Imrich H, Dorries R, Butcher GW, ter Meulen V. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A. 1991;88:7438–42.CrossRefPubMedPubMedCentral
55.
Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42:717–27.CrossRefPubMed
56.
Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007;4:e124.CrossRefPubMedPubMedCentral
57.
van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta. 1812;2011:141–50.
58.
Weber MS, Benkhoucha M, Lehmann-Horn K, Hertzenberg D, Sellner J, Santiago-Raber ML, et al. Repetitive pertussis toxin promotes development of regulatory T cells and prevents central nervous system autoimmune disease. PLoS One. 2010;5(12):e16009.CrossRefPubMedPubMedCentral
59.
Weber MS, Youssef S, Dunn SE, Prod'homme T, Neuhaus O, Stuve O, Greenwood J, Steinman L, Zamvil SS. Statins in the treatment of central nervous system autoimmune disease. J Neuroimmunol. 2006;178:140–8.CrossRefPubMed
60.
Willis CL. Glia-induced reversible disruption of blood–brain barrier integrity and neuropathological response of the neurovascular unit. Toxicol Pathol. 2010;39:172–85.CrossRefPubMed
61.
Wolburg-Buchholz K, Mack AF, Steiner E, Pfeiffer F, Engelhardt B, Wolburg H. Loss of astrocyte polarity marks blood–brain barrier impairment during experimental autoimmune encephalomyelitis. Acta Neuropathol. 2009;118:219–33.CrossRefPubMed
62.
Wraith DC, Nicolson KS, Whitley NT. Regulatory CD4+ T cells and the control of autoimmune disease. Curr Opin Immunol. 2004;16:695–701.CrossRefPubMed
63.
Zhu D, Liu M, Yang Y, Ma L, Jiang Y, Zhou L, Huang Q, Pi R, Chen X. Ginsenoside Rd ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neurosci Res. 2014;92:1217–26.CrossRefPubMed
Metadata
Title
IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier
Authors
Min Jung Lee
So Jin Bing
Jonghee Choi
Minhee Jang
Gihyun Lee
Hyunkyoung Lee
Byung Soo Chang
Youngheun Jee
Sung Joong Lee
Ik-Hyun Cho
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2016
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0116-1

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