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PMID: 11257138 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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.

The Journal of experimental medicine ·Vol. 193 ·No. 6 ·2001-03-19 ·Pages 713-26

Huang DR, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM

Abstract

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.

MeSH Terms
Amino Acid Sequence Animals CD11 Antigens/genetics CD3 Complex/genetics CD4 Antigens/genetics CD8 Antigens/genetics Cell Division Central Nervous System/metabolism,pathology Chemokine CCL2/genetics,immunology Chemokine CCL4 Chemokine CCL7 Chemokine CCL8 Chemokine CXCL10 Chemokines, CXC/biosynthesis Cytokines Encephalomyelitis, Autoimmune, Experimental/immunology Gene Expression Immunity, Innate Interferon-gamma/biosynthesis,genetics Interleukin-10/biosynthesis,genetics Interleukin-4/biosynthesis,genetics Macrophage Inflammatory Proteins/biosynthesis Macrophages/immunology Mice Mice, Inbred C57BL Mice, Knockout Molecular Sequence Data Monocyte Chemoattractant Proteins/genetics Myelin Proteins Myelin Proteolipid Protein/pharmacology Myelin-Associated Glycoprotein/pharmacology Myelin-Oligodendrocyte Glycoprotein T-Lymphocytes/cytology,drug effects Th1 Cells/immunology Up-Regulation
Chemicals
CD11 Antigens CD3 Complex CD4 Antigens CD8 Antigens Ccl12 protein, mouse Ccl7 protein, mouse Ccl8 protein, mouse Chemokine CCL2 Chemokine CCL4 Chemokine CCL7 Chemokine CCL8 Chemokine CXCL10 Chemokines, CXC Cytokines Macrophage Inflammatory Proteins Mog protein, mouse Monocyte Chemoattractant Proteins Myelin Proteins Myelin Proteolipid Protein Myelin-Associated Glycoprotein Myelin-Oligodendrocyte Glycoprotein Interleukin-10 Interleukin-4 Interferon-gamma
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Huang D R
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Wang J
Kivisakk P
Rollins B J
Ransohoff R M
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.193.6.713
Published
2001-03-19
Pages
713-26
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193420
Subset
IM
Grants
NCI NIH HHS · 2RO1 CA53091 · United States
NINDS NIH HHS · 1PO1 NS38667 · United States
NINDS NIH HHS · 2RO1 NS32151 · United States
External Links
PubMed source DOI: 10.1084/jem.193.6.713 PMC Full Text View journal details
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