Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis.
Monocyte chemoattractant protein (MCP)-1 plays a critical role in innate immunity by directing the migration of monocytes into inflammatory sites. Recent data indicated a function for this chemokine in adaptive immunity as a regulator of T cell commitment to T helper cell type 2 (Th2) effector function. Studies in a Th1-dependent animal model, experimental autoimmune encephalomyelitis (EAE), showed that MCP-1 was highly expressed in the central nervous system (CNS) of affected rodents, and MCP-1 antibodies could block relapses of the disease. Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients. We analyzed EAE in mice deficient for MCP-1 to define the relevant ligand for CCR2, which responds to murine MCP-1, MCP-2, MCP-3, and MCP-5. We found that C57BL/6 MCP-1-null mice were markedly resistant to EAE after active immunization, with drastically impaired recruitment of macrophages to the CNS, yet able to generate effector T cells that transferred severe disease to naive wild-type recipients. By contrast, adoptive transfer of primed T cells from wild-type mice into naive MCP-1-null recipients did not mediate clinical EAE. On the SJL background, disruption of the MCP-1 gene produced a milder EAE phenotype with diminished relapses that mimicked previous findings using anti-MCP-1 antibodies. There was no compensatory upregulation of MCP-2, MCP-3, or MCP-5 in MCP-1-null mice with EAE. These results indicated that MCP-1 is the major CCR2 ligand in mice with EAE, and provided an opportunity to define the role of MCP-1 in EAE. Compared with wild-type littermates, MCP-1-/- mice exhibited reduced expression of interferon gamma in draining lymph node and CNS and increased antigen-specific immunoglobulin G1 antibody production. Taken together, these data demonstrate that MCP-1 is crucial for Th1 immune responses in EAE induction and that macrophage recruitment to the inflamed CNS target organ is required for primed T cells to execute a Th1 effector program in EAE.
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
D R
DR
Huang
J
J
Wang
P
P
Kivisakk
B J
BJ
Rollins
R M
RM
Ransohoff
D000595:Amino Acid Sequence; D000818:Animals; D018845:CD11 Antigens / Q000235:genetics; D017252:CD3 Complex / Q000235:genetics; D015704:CD4 Antigens / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics; D002455:Cell Division; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology*; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis; D016207:Cytokines; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D015870:Gene Expression; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein / Q000494:pharmacology; D018992:Myelin-Associated Glycoprotein / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D018417:Th1 Cells / Q000276:immunology*; D015854:Up-Regulation
D018845:CD11 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; C491224:Ccl12 protein, mouse; C515451:Ccl7 protein, mouse; C515454:Ccl8 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; C571327:Mog protein, mouse; D018945:Monocyte Chemoattractant Proteins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma