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PMID: 10601356 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice.

The Journal of experimental medicine ·Vol. 190 ·No. 12 ·1999-12-20 ·Pages 1813-24

Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR

Abstract

Infiltrating leukocytes may be responsible for autoimmune disease. We hypothesized that the chemokine monocyte chemoattractant protein (MCP)-1 recruits macrophages and T cells into tissues that, in turn, are required for autoimmune disease. Using the MRL-Fas(lpr) strain with spontaneous, fatal autoimmune disease, we constructed MCP-1-deficient MRL-Fas(lpr) mice. In MCP-1-intact MRL-Fas(lpr) mice, macrophages and T cells accumulate at sites (kidney tubules, glomeruli, pulmonary bronchioli, lymph nodes) in proportion to MCP-1 expression. Deleting MCP-1 dramatically reduces macrophage and T cell recruitment but not proliferation, protects from kidney, lung, skin, and lymph node pathology, reduces proteinuria, and prolongs survival. Notably, serum immunoglobulin (Ig) isotypes and kidney Ig/C3 deposits are not diminished in MCP-1-deficient MRL-Fas(lpr) mice, highlighting the requirement for MCP-1-dependent leukocyte recruitment to initiate autoimmune disease. However, MCP-1-deficient mice are not completely protected from leukocytic invasion. T cells surrounding vessels with meager MCP-1 expression remain. In addition, downstream effector cytokines/chemokines are decreased in MCP-1-deficient mice, perhaps reflecting a reduction of cytokine-expressing leukocytes. Thus, MCP-1 promotes MRL-Fas(lpr) autoimmune disease through macrophage and T cell recruitment, amplified by increasing local cytokines/chemokines. We suggest that MCP-1 is a principal therapeutic target with which to combat autoimmune diseases.

MeSH Terms
Animals Autoimmune Diseases/genetics,immunology Chemokine CCL2/deficiency,genetics,immunology Gene Deletion Gene Expression Regulation/immunology Macrophages/immunology Mice Mice, Inbred MRL lpr T-Lymphocytes/immunology
Chemicals
Chemokine CCL2
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tesch G H
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Maifert S
Schwarting A
Rollins B J
Kelley V R
References (45)
45 references, click to expand
  1. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant.
    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652-6 PMID: 8170963
  2. Murine models of systemic lupus erythematosus.
    Adv Immunol. 1985;37:269-390 PMID: 3890479
  3. Two histopathologic types of inflammatory vascular disease in MRL/Mp autoimmune mice. Model for human vasculitis in connective tissue disease.
    Arthritis Rheum. 1985 Oct;28(10):1146-55 PMID: 4052126
  4. The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice.
    J Exp Med. 1988 May 1;167(5):1713-8 PMID: 3259258
  5. Purification of a monocyte chemotactic factor secreted by nonhuman primate vascular cells in culture.
    Biochemistry. 1988 May 31;27(11):4162-8 PMID: 3415979
  6. An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity.
    J Exp Med. 1991 Jun 1;173(6):1441-9 PMID: 2033370
  7. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis.
    Nature. 1992 Mar 26;356(6367):314-7 PMID: 1372394
  8. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes.
    J Immunol. 1992 Apr 15;148(8):2423-8 PMID: 1348518
  9. Unmodified pancreatic islet allograft rejection results in the preferential expression of certain T cell activation transcripts.
    J Immunol. 1993 Feb 1;150(3):1093-104 PMID: 8423334
  10. IgG3 cryoglobulins in autoimmune MRL-lpr/lpr mice: immunopathogenesis, therapeutic approaches and relevance to similar human diseases.
    Ann Rheum Dis. 1993 Mar;52 Suppl 1:S48-54 PMID: 8481059
  11. Colony stimulating factor-1 in the induction of lupus nephritis.
    Kidney Int. 1993 May;43(5):1000-9 PMID: 8510378
  12. Autoimmune disease in mice due to integration of an endogenous retrovirus in an apoptosis gene.
    J Exp Med. 1993 Aug 1;178(2):461-8 PMID: 7688023
  13. Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium.
    Clin Immunol Immunopathol. 1993 Oct;69(1):83-91 PMID: 8403545
  14. Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice.
    J Immunol. 1993 Dec 1;151(11):6509-16 PMID: 7902378
  15. Production of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha by inflammatory granuloma fibroblasts.
    Am J Pathol. 1994 Apr;144(4):711-8 PMID: 8160772
  16. Glomerular expression of monocyte chemoattractant protein-1 in experimental and human glomerulonephritis.
    Lab Invest. 1994 Oct;71(4):536-42 PMID: 7967509
  17. Induction of natural killer cell migration by monocyte chemotactic protein-1, -2 and -3.
    Eur J Immunol. 1994 Dec;24(12):3233-6 PMID: 7805752
  18. A role for C-C chemokines in fibrotic lung disease.
    J Leukoc Biol. 1995 May;57(5):782-7 PMID: 7539030
  19. Murine lupus in MRL/lpr mice lacking CD4 or CD8 T cells.
    Eur J Immunol. 1995 Sep;25(9):2558-62 PMID: 7589126
  20. Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production.
    J Leukoc Biol. 1996 Jan;59(1):81-9 PMID: 8558072
  21. Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat.
    J Immunol. 1996 Apr 15;156(8):3017-23 PMID: 8609424
  22. Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis.
    Kidney Int. 1996 Mar;49(3):761-7 PMID: 8648917
  23. Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy.
    J Immunol. 1996 Jul 1;157(1):433-40 PMID: 8683149
  24. Macrophage growth factors introduced into the kidney initiate renal injury.
    Mol Med. 1996 May;2(3):297-312 PMID: 8784783
  25. Distinct expression and function of the novel mouse chemokine monocyte chemotactic protein-5 in lung allergic inflammation.
    J Exp Med. 1996 Nov 1;184(5):1939-51 PMID: 8920881
  26. Production of macrophage colony-stimulating factor by murine liver in vivo.
    Cytokine. 1997 Jan;9(1):53-8 PMID: 9067096
  27. RANTES and monocyte chemoattractant protein-1 (MCP-1) play an important role in the inflammatory phase of crescentic nephritis, but only MCP-1 is involved in crescent formation and interstitial fibrosis.
    J Exp Med. 1997 Apr 7;185(7):1371-80 PMID: 9104823
  28. Differential recruitment of leukocyte populations and alteration of airway hyperreactivity by C-C family chemokines in allergic airway inflammation.
    J Immunol. 1997 May 1;158(9):4398-404 PMID: 9127004
  29. IFN-gamma is essential for the development of autoimmune glomerulonephritis in MRL/Ipr mice.
    J Immunol. 1997 Jun 1;158(11):5484-91 PMID: 9164971
  30. Renal expression of monocyte chemoattractant protein-1 in lupus autoimmune mice.
    J Am Soc Nephrol. 1997 May;8(5):720-9 PMID: 9176841
  31. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model.
    J Exp Med. 1997 Jul 7;186(1):131-7 PMID: 9207007
  32. Gene expression of CC chemokines in experimental crescentic glomerulonephritis (CGN).
    Clin Exp Immunol. 1997 Jul;109(1):143-8 PMID: 9218837
  33. Chemokines.
    Blood. 1997 Aug 1;90(3):909-28 PMID: 9242519
  34. Intercellular adhesion molecule-1 deficiency protects MRL/MpJ-Fas(lpr) mice from early lethality.
    J Immunol. 1997 Aug 15;159(4):2058-67 PMID: 9257874
  35. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice.
    J Exp Med. 1998 Feb 16;187(4):601-8 PMID: 9463410
  36. IFN-gamma limits macrophage expansion in MRL-Fas(lpr) autoimmune interstitial nephritis: a negative regulatory pathway.
    J Immunol. 1998 Apr 15;160(8):4074-81 PMID: 9558118
  37. Monocyte chemoattractant protein-1 synthesis by murine lung fibroblasts modulates CD4+ T cell activation.
    J Immunol. 1998 May 1;160(9):4606-14 PMID: 9574568
  38. Gene transfer of RANTES elicits autoimmune renal injury in MRL-Fas(1pr) mice.
    Kidney Int. 1998 Jun;53(6):1631-41 PMID: 9607194
  39. Chemotactic factors and renal inflammation.
    Am J Kidney Dis. 1998 Jun;31(6):1065-84 PMID: 9631856
  40. IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas(lpr) mice.
    J Immunol. 1998 Jul 1;161(1):494-503 PMID: 9647261
  41. The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness.
    J Exp Med. 1998 Jul 6;188(1):157-67 PMID: 9653092
  42. CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines.
    J Clin Invest. 1998 Sep 15;102(6):1112-24 PMID: 9739045
  43. Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice.
    J Immunol. 1998 Oct 1;161(7):3767-75 PMID: 9759903
  44. Regulation of T lymphocyte trafficking into lymph nodes during an immune response by the chemokines macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta.
    J Immunol. 1998 Nov 15;161(10):5663-72 PMID: 9820547
  45. Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis.
    J Clin Invest. 1999 Jan;103(1):73-80 PMID: 9884336
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.190.12.1813
Published
1999-12-20
Pages
1813-24
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2195716
Subset
IM
Grants
NIDDK NIH HHS · DK 52369 · United States
NIDDK NIH HHS · DK-36149 · United States
External Links
PubMed source DOI: 10.1084/jem.190.12.1813 PMC Full Text View journal details
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