C) Mean EAE clinical score is shown for groups (n =3) of WT mice reconstituted with mixtures of BM cells from your indicated donors. data suggest that CCR2-dependent DC recruitment to the CNS during ongoing neuroinflammation plays a crucial role in effector T cell cytokine production Anle138b and disease progression, and signify that CNS-DCs and circulating DC precursors might be important therapeutic targets for suppressing ongoing neuroinflammation in CNS autoimmune diseases. INTRODUCTION Dendritic cells (DCs) are antigen (Ag) presenting cells (APCs) capable of migrating from organ tissues to regional lymph nodes (LNs) and stimulating T cells to promote both tolerance and immunity to self and foreign Ag acquired in situ. In addition to their role in regulating adaptive immune responses in peripheral lymphoid organ (PLO) tissues, DCs accumulate in inflamed tissues where they are thought to present MHC class II-restricted Ag to co-infiltrating CD4+ effector T cells (1C3). We as well ITGAV as others have shown that DCs accumulate in perivascular spaces Anle138b and within inflammatory foci Anle138b in mouse models of stroke, multiple sclerosis, epilepsy, and traumatic brain injury, or after intracerebral injection of antigen or cytokines (4C14). In the context of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, CD11b+CD11c+ myeloid DCs, which are derived from blood monocytes, represent the majority of these accumulating DCs (11, 13, 15). Recruitment of immature DCs to the CNS during EAE was also shown to be dependent upon alpha-4 beta-1 integrin, which binds to VCAM-1 on brain endothelium (16). Ex lover vivo assays suggest these DCs may be important for cross-presentation of MHC class I-restricted Ag to CD8+ T cells and restimulation of CD4+ T cells with MHC class II-restricted myelin Ag (11, 17, 18). Yet, how these inflammatory DCs home to the CNS remains unclear, and whether these cells are essential tissue APCs for in situ reactivation of CNS-infiltrating T cells is usually unknown. Despite much research, no report to date has definitively recognized chemokines and chemokine receptors that may contribute to DC migration across the endothelial blood brain barrier and into the perivascular space of the CNS post-capillary venules. Chemokine receptor CCR2 is usually expressed on monocytes, monocytoid DC precursors and circulating blood DCs (19). One recent study found that human monocyte-derived DCs migrate across brain vascular endothelial cells in response to CCL2 Anle138b and that DCs were distributed adjacent to CCL2 in the CNS of mice with EAE (20). CCR2 has also been previously implicated in the migration of monocytes and myeloid DCs to inflammatory sites including: infected lung (21C23), psoriasis (19, 24), diabetes mellitus (25), and rheumatoid arthritis (26, 27). In CNS tissues, it was shown that astrocyte-specific overexpression of the CCR2 ligand CCL2 prospects to spontaneous asymptomatic accumulation of perivascular monocytes in the brain with little infiltration into the CNS Anle138b parenchyma (28). In relapsing-remitting EAE in Lewis rats, CCL2 expression correlates with disease relapse (29). Similarly, CCL2?/? mice have impaired monocyte recruitment to CNS perivascular spaces during CNS viral contamination (30). Consistent with this, CCR2?/? mice are guarded from EAE and bone marrow chimera experiments revealed that host CCL2 deficiency but not donor deficiency guarded mice from EAE by reducing the recruitment of monocytes and myeloid DCs (31), suggesting the CCL2-CCR2 axis may be important for myeloid cell recruitment to the perivascular spaces of the inflamed CNS. Additionally, whereas adoptively transferred CCR2?/? T cells are capable of inducing EAE in Wild Type (WT) mice, WT T cells are incapable of inducing EAE in CCR2?/? mice. This implies that CCR2 is required on one or more immune cell subsets other than T cells for disease onset (22, 32, 33). However, the potential role of CCR2 in recruiting myeloid DCs to the CNS remains unknown and has been largely overshadowed by the marked amelioration of EAE disease progression associated with reduced monocyte recruitment to.