Experimental autoimmune encephalomyelitis (EAE) is an infl ammatory demyelinating disease of the central nervous system (CNS) induced in laboratory animals by active immunization with myelin antigens or by the adoptive transfer of myelin-specifi c CD4 + T cells. It is widely used as an animal model of multiple sclerosis (MS) and as a prototype of organ-specifi c autoimmunity. Until recently, EAE and MS were considered Th1 diseases, mediated by IL-12p70 -polarized, IFN-␥ -producing eff ector cells. This impression was based, in large part, on the association between clinical disease activity and expression of IFN-␥ and IL-12p40 (a subunit of IL-12p70) in CNS tissues, cerebrospinal fl uid, and circulating leukocytes ( 1 -3 ). In addition, activated macrophages are the predominant leukocyte in CNS infi ltrates of affl icted animals and patients, similar to the infi ltrates that characterize Th1-dependent hypersensitivity and antimicrobial responses in the periphery ( 4, 5 ).Recent fi ndings, however, suggest that the cytokine pathways underlying encephalitogenic T cell development and function are more complex than previously appreciated. Defi ciency of IL-17 or IL-23 (a heterodimeric monokine composed of IL-12p40 and p19 chains that expands and/or stabilizes Th17 cells) ( 6, 7 ) confers partial or complete resistance, respectively, against MOG 35-55 -induced EAE in C57BL/6 mice, whereas defi ciency of IFN-␥ or IL-12p70 does not ( 8 -10 ). Furthermore, myelin-specifi c

Mature myeloid cells (macrophages andCD11b IntroductionMyeloid cells, such as macrophages and dendritic cells (DCs), are a prominent constituent of inflammatory infiltrates in the central nervous system (CNS) during multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). 1,2 These cells not only serve as antigen-presenting cells for the reactivation of infiltrating myelin-reactive CD4 ϩ T cells but are thought to directly inflict tissue damage through secretion of toxic factors, such as reactive oxygen species, proteases, and tumor necrosis factor-␣ (TNF-␣). 3,4 They might also recruit naive myelin-reactive T cells into the effector pool in the context of epitope spreading. 5 We and others have demonstrated that bone marrow-derived CD11c ϩ major histocompatibility complex (MHC) class II ϩ DCs accumulate in the CNS during EAE and have the capacity to polarize naive T cells along encephalitogenic Th1 and Th17 lineages. 2,6 However, the circulating cell that gives rise to CNS-infiltrating DCs and macrophages has yet to be defined. The specific chemokine pathways and adhesion molecule interactions required for infiltration of the CNS by myeloid cells will depend on whether they cross the blood-brain barrier as immature monocytes or as macrophages and DCs. Therefore, identification of the differentiation status of the migrating cell holds implications regarding candidate therapeutic targets in neuroinflammatory diseases, such as multiple sclerosis (MS).Under steady-state conditions, mature myeloid lineages are maintained within lymphoid and peripheral tissues through controlled release of bone marrow progenitors/precursors into the peripheral circulation. 7 In the setting of infection or injury, myeloid cell mobilization is accelerated to meet the demands imposed by the increased turnover of macrophages and DCs at the site of inflammation. 8,9 The pathways underlying expansion of peripheral myeloid cell pools under stress are thought to serve an adaptive role by reinforcing host protection against infectious agents and by promoting wound healing. 8 Conversely, leukocyte-mobilizing pathways might be subverted to sustain target organ inflammation during relapsing or chronic autoimmune disease. For example, the number of macrophages and DCs in the CNS contracts during remissions and rebounds during exacerbations of EAE, suggesting that myeloid precursors might be released at a heightened rate before, or in concert with, clinical disease activity. 10,11 Recently, it was shown that CCL2 expression by nonhematopoetic (likely glial) cells is important for the accumulation of proinflammatory DCs in the CNS during acute EAE. 12 Furthermore, transgenic animals that simultaneously express CCL2 in the CNS and Fms-like tyrosine kinase 3 ligand in the periphery spontaneously develop meningeal and perivascular inflammation in association with an ascending paralysis. The neuroinflammation in this model appears to be primarily driven by myeloid cells and occurs independent of T and B lymphocytes. 13 The receptor ...

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The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.