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

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 γ 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.

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…Nonetheless, the preferential reduction of the levels of anti-AChR IgG2b suggested altered Th cell function. CCL2 plays a role in the development of both Th2 and Th1 cells [11,23]. In our model, IFN-c production by CD4 + T and CD8 + T cells in response to AChR stimulation was marginally impaired in CCL2 -/-mice ( Fig.…”

“…The involvement of CCL2 in several experimental models of inflammation and autoimmunity is well established, and appears to partly depend on the ability of this chemokine to direct the inflammatory influx to target organs and to promote Th1 and/or Th2 cells [10][11][12][13]. The autoimmune model of EAMG differs from the other systems studied for at least two reasons.…”

“…Antibodies to AChR are ultimately responsible for the block at the neuromuscular junction that leads to muscular weakness. It will be important to address next whether CCL2 may be a specific therapeutic target to modulate clinical MG. Mice C57BL/6 (B6) mice deficient of MCP-1 (MCP-1 -/-) [11], IL-6 (IL-6 -/-), IFN (IFN-c -/-) and RAG (RAG-c -/-) [30] were purchased from The Jackson Laboratory (Bar Harbor, ME). IL-17 -/-mice were provided by Dr. Yoichiro Iwakura [5].…”

“…CCL2 exerts its function through its receptor CCR2 in vivo [11,13]. CCR2 expression has been recently described on B cells and influences B cell functions [21,22].…”

“…The CC chemokine ligand 2 (CCL2), initially known as monocyte chemoattractant protein 1 (MCP-1), is expressed by inflammatory cells at sites of tissue injury [10][11][12][13]. CCL2 directs the migration of monocytes, dendritic cells, NK cells and T cells, and coordinates inflammatory responses during infection [13].…”