QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 3, 2007, 27(40):10714-10721; doi:10.1523/JNEUROSCI.1922-07.2007

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Ponomarev, E. D. Articles by Dittel, B. N. Search for Related Content PubMed PubMed Citation Articles by Ponomarev, E. D. Articles by Dittel, B. N.

 Previous Article  |  Next Article 

Neurobiology of Disease
CNS-Derived Interleukin-4 Is Essential for the Regulation of Autoimmune Inflammation and Induces a State of Alternative Activation in Microglial Cells

Eugene D. Ponomarev, ^* Katarzyna Maresz, ^* Yanping Tan, and Bonnie N. Dittel

BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, Wisconsin 53201-2178

Correspondence should be addressed to Dr. Bonnie N. Dittel, P.O. Box 2178, Milwaukee, WI 53201-2178. Email: bonnie.dittel{at}bcw.edu

Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in neurodegenerative diseases such as multiple sclerosis (MS). We investigated the role of interleukin-4 (IL-4) in regulating CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells. We also found that CNS-resident microglial cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated macrophages (aaMs), in an IL-4-dependent manner. This aaM phenotype extended to the lack of nitric oxide (NO) production by activated microglial cells, which is a marker of classically activated macrophages. We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, macrophages that migrate into the CNS exhibit a dual phenotype. These data indicate that IL-4 production in the CNS is essential for controlling autoimmune inflammation by inducing a microglial cell aaM phenotype. Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for microglial cells in the regulation of inflammation in the CNS.

Key words: activation; autoimmunity; encephalomyelitis; interleukin; macrophage; microglia; multiple sclerosis; neuroinflammation

---

Received April 27, 2007; revised Aug. 12, 2007; accepted Aug. 20, 2007.

Correspondence should be addressed to Dr. Bonnie N. Dittel, P.O. Box 2178, Milwaukee, WI 53201-2178. Email: bonnie.dittel{at}bcw.edu

This article has been cited by other articles:

				C. Kadoch, E. B. Dinca, R. Voicu, L. Chen, D. Nguyen, S. Parikh, J. Karrim, M. A. Shuman, C. A. Lowell, P. A. Treseler, et al. Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model Clin. Cancer Res., March 15, 2009; 15(6): 1989 - 1997. [Abstract] [Full Text] [PDF]

				B. R. Tambuyzer, P. Ponsaerts, and E. J. Nouwen Microglia: gatekeepers of central nervous system immunology J. Leukoc. Biol., March 1, 2009; 85(3): 352 - 370. [Abstract] [Full Text] [PDF]

				W. Stenzel, U. Muller, G. Kohler, F. L. Heppner, M. Blessing, A. N.J. McKenzie, F. Brombacher, and G. Alber IL-4/IL-13-Dependent Alternative Activation of Macrophages but Not Microglial Cells Is Associated with Uncontrolled Cerebral Cryptococcosis Am. J. Pathol., February 1, 2009; 174(2): 486 - 496. [Abstract] [Full Text] [PDF]

				C. Lambert, J. Desbarats, N. Arbour, J. A. Hall, A. Olivier, A. Bar-Or, and J. P. Antel Dendritic Cell Differentiation Signals Induce Anti-Inflammatory Properties in Human Adult Microglia J. Immunol., December 15, 2008; 181(12): 8288 - 8297. [Abstract] [Full Text] [PDF]

				S. Jimenez, D. Baglietto-Vargas, C. Caballero, I. Moreno-Gonzalez, M. Torres, R. Sanchez-Varo, D. Ruano, M. Vizuete, A. Gutierrez, and J. Vitorica Inflammatory Response in the Hippocampus of PS1M146L/APP751SL Mouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic J. Neurosci., November 5, 2008; 28(45): 11650 - 11661. [Abstract] [Full Text] [PDF]

				D. R. Beers, J. S. Henkel, W. Zhao, J. Wang, and S. H. Appel CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS PNAS, October 7, 2008; 105(40): 15558 - 15563. [Abstract] [Full Text] [PDF]

				H. Ohtaki, J. H. Ylostalo, J. E. Foraker, A. P. Robinson, R. L. Reger, S. Shioda, and D. J. Prockop Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses PNAS, September 23, 2008; 105(38): 14638 - 14643. [Abstract] [Full Text] [PDF]

				K. A. Shirey, L. E. Cole, A. D. Keegan, and S. N. Vogel Francisella tularensis Live Vaccine Strain Induces Macrophage Alternative Activation as a Survival Mechanism J. Immunol., September 15, 2008; 181(6): 4159 - 4167. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help