CC Chemokine Receptor 4 is Required for Experimental Autoimmune Encephalomyelitis by Regulating GM-CSF and IL-23 Production in Dendritic Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Feb 23

PMID 22355103

Citations 33

Authors

Karola Poppensieker

David-Marian Otte

Britta Schurmann

Andreas Limmer

Philipp Dresing

Eva Drews

Beatrix Schumak

Luisa Klotz

Jennifer Raasch

Alexander Mildner

Ari Waisman

Stefanie Scheu

Percy Knolle

Irmgard Forster

Marco Prinz

Wolfgang Maier

Andreas Zimmer

Judith Alferink

Affiliations

Soon will be listed here.

Abstract

Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4(-/-) mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4(-/-) mice, indicating that CCR4(+) DCs are cellular mediators of EAE development. Mechanistically, CCR4(-/-) DCs were less efficient in GM-CSF and IL-23 production and also T(H)-17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4(-/-) mice, whereas intracerebral inoculation using IL-23(-/-) DCs or GM-CSF(-/-) DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.

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References

Segal B . Th17 cells in autoimmune demyelinating disease. Semin Immunopathol. 2010; 32(1):71-7. PMC: 2874248. DOI: 10.1007/s00281-009-0186-z. View

Wekerle H . Lessons from multiple sclerosis: models, concepts, observations. Ann Rheum Dis. 2008; 67 Suppl 3:iii56-60. DOI: 10.1136/ard.2008.098020. View

Sallusto F, Baggiolini M . Chemokines and leukocyte traffic. Nat Immunol. 2008; 9(9):949-52. DOI: 10.1038/ni.f.214. View

Langrish C, Chen Y, Blumenschein W, Mattson J, Basham B, Sedgwick J . IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005; 201(2):233-40. PMC: 2212798. DOI: 10.1084/jem.20041257. View

Izikson L, Klein R, Luster A, Weiner H . Targeting monocyte recruitment in CNS autoimmune disease. Clin Immunol. 2002; 103(2):125-31. DOI: 10.1006/clim.2001.5167. View

Forde E, Dogan R, Karpus W . CCR4 contributes to the pathogenesis of experimental autoimmune encephalomyelitis by regulating inflammatory macrophage function. J Neuroimmunol. 2011; 236(1-2):17-26. PMC: 3139027. DOI: 10.1016/j.jneuroim.2011.04.008. View

Bettelli E, Pagany M, Weiner H, Linington C, Sobel R, Kuchroo V . Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J Exp Med. 2003; 197(9):1073-81. PMC: 2193967. DOI: 10.1084/jem.20021603. View

Dogan R, Long N, Forde E, Dennis K, Kohm A, Miller S . CCL22 regulates experimental autoimmune encephalomyelitis by controlling inflammatory macrophage accumulation and effector function. J Leukoc Biol. 2010; 89(1):93-104. PMC: 3004518. DOI: 10.1189/jlb.0810442. View

Butti E, Bergami A, Recchia A, Brambilla E, Del Carro U, Amadio S . IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis. Gene Ther. 2008; 15(7):504-15. DOI: 10.1038/gt.2008.10. View

10.

Henry C, Ornelles D, Mitchell L, Brzoza-Lewis K, Hiltbold E . IL-12 produced by dendritic cells augments CD8+ T cell activation through the production of the chemokines CCL1 and CCL17. J Immunol. 2008; 181(12):8576-84. PMC: 2716729. DOI: 10.4049/jimmunol.181.12.8576. View

11.

Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Capello E, Mancardi G . Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol. 2006; 65(2):124-41. DOI: 10.1097/01.jnen.0000199572.96472.1c. View

12.

Narikawa K, Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y . CSF chemokine levels in relapsing neuromyelitis optica and multiple sclerosis. J Neuroimmunol. 2004; 149(1-2):182-6. DOI: 10.1016/j.jneuroim.2003.12.010. View

13.

Mildner A, Mack M, Schmidt H, Bruck W, Djukic M, Zabel 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. DOI: 10.1093/brain/awp144. View

14.

Yuan Q, Bromley S, Means T, Jones K, Hayashi F, Bhan A . CCR4-dependent regulatory T cell function in inflammatory bowel disease. J Exp Med. 2007; 204(6):1327-34. PMC: 2118617. DOI: 10.1084/jem.20062076. View

15.

Lassmann H . Models of multiple sclerosis: new insights into pathophysiology and repair. Curr Opin Neurol. 2008; 21(3):242-7. DOI: 10.1097/WCO.0b013e3282fee94a. View

16.

Alferink J, Lieberam I, Reindl W, Behrens A, Weiss S, Huser N . Compartmentalized production of CCL17 in vivo: strong inducibility in peripheral dendritic cells contrasts selective absence from the spleen. J Exp Med. 2003; 197(5):585-99. PMC: 2193819. DOI: 10.1084/jem.20021859. View

17.

Zozulya A, Ortler S, Lee J, Weidenfeller C, Sandor M, Wiendl H . Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS. J Neurosci. 2009; 29(1):140-52. PMC: 2942091. DOI: 10.1523/JNEUROSCI.2199-08.2009. View

18.

Cua D, Sherlock J, Chen Y, Murphy C, Joyce B, Seymour B . Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003; 421(6924):744-8. DOI: 10.1038/nature01355. View

19.

Romagnani S . Cytokines and chemoattractants in allergic inflammation. Mol Immunol. 2002; 38(12-13):881-5. DOI: 10.1016/s0161-5890(02)00013-5. View

20.

Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M . GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J Exp Med. 2008; 205(10):2281-94. PMC: 2556786. DOI: 10.1084/jem.20071119. View