Impaired Monocyte Migration and Reduced Type 1 (Th1) Cytokine Responses in C-C Chemokine Receptor 2 Knockout Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1997 Nov 20

PMID 9366570

Citations 427

Authors

L Boring

J Gosling

S W Chensue

S L Kunkel

R V Farese Jr

H E Broxmeyer

I F Charo

Affiliations

Soon will be listed here.

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease. To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1. CCR2-/- mice were born at the expected Mendelian ratios and developed normally. In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. In in vitro chemotaxis assays, CCR2-/- leukocytes failed to migrate in response to MCP-1. Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis. As compared with wild-type littermates, CCR2-/- mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes. Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2-/- mice and in naive splenocytes activated by concanavalin A. We conclude that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines. These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.

Citing Articles

The role of myeloid cell heterogeneity during spontaneous choroidal neovascularization in Vldlr knockout mice.

Rajesh A, Gong J, Chan K, Viniak R, Droho S, Kachar D J Neuroinflammation. 2025; 22(1):70.

PMID: 40055675 PMC: 11889776. DOI: 10.1186/s12974-025-03398-3.

CCL2/CCR2 Signalling in Mesenchymal Stem/Progenitor Cell Recruitment and Fracture Healing in Mice.

Kannan R, Koh A, Kent 3rd R, Bhutada K, Wasi F, Wagner L J Cell Mol Med. 2024; 28(24):e70300.

PMID: 39721002 PMC: 11669326. DOI: 10.1111/jcmm.70300.

Ezrin drives adaptation of monocytes to the inflamed lung microenvironment.

Gudneppanavar R, Di Pietro C, H Oz H, Zhang P, Cheng E, Huang P Cell Death Dis. 2024; 15(11):864.

PMID: 39613751 PMC: 11607083. DOI: 10.1038/s41419-024-07255-8.

Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.

Cruz Tleugabulova M, Melo S, Wong A, Arlantico A, Liu M, Webster J Nat Commun. 2024; 15(1):9575.

PMID: 39505846 PMC: 11541919. DOI: 10.1038/s41467-024-53700-9.

Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells.

Huang H, Chen Y, Zhao C, Zheng X, Yu K, Yue J Nat Commun. 2024; 15(1):9337.

PMID: 39472435 PMC: 11522483. DOI: 10.1038/s41467-024-53659-7.

References

Yla-Herttuala S, Lipton B, Rosenfeld M, Sarkioja T, Yoshimura T, Leonard E . Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A. 1991; 88(12):5252-6. PMC: 51850. DOI: 10.1073/pnas.88.12.5252. View

Grewal I, RUTLEDGE B, Fiorillo J, Gu L, Gladue R, Flavell R . Transgenic monocyte chemoattractant protein-1 (MCP-1) in pancreatic islets produces monocyte-rich insulitis without diabetes: abrogation by a second transgene expressing systemic MCP-1. J Immunol. 1997; 159(1):401-8. View

Nelken N, Coughlin S, Gordon D, Wilcox J . Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991; 88(4):1121-7. PMC: 295565. DOI: 10.1172/JCI115411. View

Maze R, Sherry B, Kwon B, Cerami A, Broxmeyer H . Myelosuppressive effects in vivo of purified recombinant murine macrophage inflammatory protein-1 alpha. J Immunol. 1992; 149(3):1004-9. View

Koch A, Kunkel S, Harlow L, Johnson B, Evanoff H, Haines G . Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest. 1992; 90(3):772-9. PMC: 329929. DOI: 10.1172/JCI115950. View

Kuna P, Reddigari S, Schall T, Rucinski D, Sadick M, Kaplan A . Characterization of the human basophil response to cytokines, growth factors, and histamine releasing factors of the intercrine/chemokine family. J Immunol. 1993; 150(5):1932-43. View

Taub D, Conlon K, Lloyd A, Oppenheim J, Kelvin D . Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science. 1993; 260(5106):355-8. DOI: 10.1126/science.7682337. View

Ross R . The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362(6423):801-9. DOI: 10.1038/362801a0. View

Ishibashi S, Brown M, Goldstein J, Gerard R, Hammer R, Herz J . Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993; 92(2):883-93. PMC: 294927. DOI: 10.1172/JCI116663. View

10.

Paul W, Seder R . Lymphocyte responses and cytokines. Cell. 1994; 76(2):241-51. DOI: 10.1016/0092-8674(94)90332-8. View

11.

Ernst C, Zhang Y, Hancock P, RUTLEDGE B, Corless C, Rollins B . Biochemical and biologic characterization of murine monocyte chemoattractant protein-1. Identification of two functional domains. J Immunol. 1994; 152(7):3541-9. View

12.

Charo I, Myers S, Herman A, Franci C, Connolly A, Coughlin S . Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci U S A. 1994; 91(7):2752-6. PMC: 43448. DOI: 10.1073/pnas.91.7.2752. View

13.

CARR M, Roth S, Luther E, ROSE S, Springer T . Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994; 91(9):3652-6. PMC: 43639. DOI: 10.1073/pnas.91.9.3652. View

14.

Murphy P . The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 1994; 12:593-633. DOI: 10.1146/annurev.iy.12.040194.003113. View

15.

Gerard C, Gerard N . C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol. 1994; 12:775-808. DOI: 10.1146/annurev.iy.12.040194.004015. View

16.

Franci C, Wong L, Van Damme J, Proost P, Charo I . Monocyte chemoattractant protein-3, but not monocyte chemoattractant protein-2, is a functional ligand of the human monocyte chemoattractant protein-1 receptor. J Immunol. 1995; 154(12):6511-7. View

17.

Cook D, Beck M, Coffman T, Kirby S, Sheridan J, Pragnell I . Requirement of MIP-1 alpha for an inflammatory response to viral infection. Science. 1995; 269(5230):1583-5. DOI: 10.1126/science.7667639. View

18.

Karpus W, Lukacs N, McRae B, Strieter R, Kunkel S, Miller S . An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol. 1995; 155(10):5003-10. View

19.

Broxmeyer H, Cooper S, Hague N, Benninger L, Sarris A, Cornetta K . Human chemokines: enhancement of specific activity and effects in vitro on normal and leukemic progenitors and a factor-dependent cell line and in vivo in mice. Ann Hematol. 1995; 71(5):235-46. DOI: 10.1007/BF01744373. View

20.

Combadiere C, Ahuja S, Van Damme J, Tiffany H, Gao J, Murphy P . Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2B. J Biol Chem. 1995; 270(50):29671-5. DOI: 10.1074/jbc.270.50.29671. View