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…

By Deren Huang, Jintang Wang, P. Kivisakk, B. Rollins, R. Ransohoff. Journal of Experimental Medicine, 2001

656 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/c480cba53c6777033b44bf0c014396f900d368bf

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In Immunology

1. D. Cua
2. TA Wynn
3. C. Tato
4. P. Murray
5. M. McGeachy
6. T. Mcclanahan
7. W. Blumenschein
8. Yi Chen

In Oncology

1. P. Murray
2. P. Kivisäkk
3. D. Cua
4. TA Wynn
5. G. Kidd
6. R. Ransohoff

Citations in the corpus

• Immune function of astrocytes (2001, background): “Mice deficient in CCR2 are resistant to EAE (Fife et al., 2000; Izikson et al., 2000), as are MCP-1-deficient mice (Huang et al., 2001), indicating the importance of MCP-1 and its receptor in the disease of EAE.”
• Astrocyte crosstalk in CNS inflammation (2020, background): “For example, astrocyte-derived CCL2 is critical for both the onset (Huang et al., 2001) and the progression of EAE (Kim et al.”
• Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. (2003, background): “Another interesting candidate is MCP-1, an essential signal for macrophage activation and recruitment (44).”
• Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation (2009, background): “Despite the redundancy in the chemokine system, others have also identified the MCP-1/CCL2CCR2 axis as being vital in driving cerebral monocyte infiltration in models of CNS inflammatory pathologies, including experimental autoimmune encephalitis (Izikson et al., 2000; Huang et al., 2001) and human ”
• Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. (2007, neutral): “Similar impairments in monocyte migration have been reported in mice lacking MCP-1 (CC chemokine ligand 2 [CCL2]), a major ligand for CCR2 (8, 9).”
• TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology (2007, background): “Nevertheless, the overall pattern of downregulation by TGF-β and IL-6 and the known associations with EA”
• Three or more routes for leukocyte migration into the central nervous system (2003, result): “Mice that lacked either CCR2 or one of its ligands, CCL2, were relatively resistant to the development of EAE, despite having T-cell responses that were equivalent to those observed in wild-type mic”
• Protective and pathogenic functions of macrophage subsets (2011, background): “Macrophages recruited to the CNS prime T cells to execute a T H 1 effector programme in EA”
• Astrocytes: Key Regulators of Neuroinflammation. (2016, background): “The chemokine CCL2 appears to be critical for EAE onset, since CCL2-deficient mice are protected from disease [81].”