CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

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.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...

Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

“…We demonstrated before that the CCL17/CCR4 axis affects the function of CCR4 ϩ myeloid cells, but not T lymphocytes, recruited into the brain during CNS autoimmunity (64). It is thus possible that CCL17 favors brain recruitment or function of myeloid cells rather than CD8…”

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

“…At the level of transcriptional profiling this has been indicated by direct comparison of defined DC subsets from different lymphoid organs [11]. We have shown that the inflammatory chemokine CCL17, a ligand of CCR4, marks a population of CD8α [18,19], and participate in cytokine-dependent Th17 differentiation [20].…”

“…At the level of transcriptional profiling this has been indicated by direct comparison of defined DC subsets from different lymphoid organs [11]. We have shown that the inflammatory chemokine CCL17, a ligand of CCR4, marks a population of CD8α [18,19], and participate in cytokine-dependent Th17 differentiation [20].In the present study, we intended to identify the molecular factors, which regulate CCL17 expression in resident CD8 − CD11b + DCs of the spleen as compared to the corresponding LN DCs. Based on characteristic differences in genome-wide expression profiling, we show that suppression of CCL17 production in the spleen is mediated through IFN-γ and that LN DCs can escape from this suppression by downregulation of the IFN-γR.…”

Reply to Othy et al.: Dendritic cell-specific expression of CCR4 is required for development of EAE

“…Thus, they give a warning on rapid translational studies. The most important aspect of our study was the finding that dendritic cells (DCs) are the relevant cellular subset mediating CCR4-dependent effects in experimental autoimmune encephalomyelitis (EAE) development (2). This prominent role of CCR4-expressing DCs in EAE was unexpected, because DCs expressed only low levels of CCR4 compared with T-cell subsets.…”

“…We appreciate the comments of Othy et al (1) in response to our recently published article (2). The authors treated myelin oligodendrocyte glycoprotein (MOG)-immunized mice with CC chemokine receptor 4 (CCR4) antagonists and did not observe an altered course of disease (1).…”