Pharmacological Blockade of CCR1 Ameliorates Murine Arthritis and Alters Cytokine Networks in Vivo

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2006 Oct 4

PMID 17016504

Citations 41

Authors

M Amat

C F Benjamim

L M Williams

N Prats

E Terricabras

J Beleta

S L Kunkel

N Godessart

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: The chemokine receptor CCR1 is a potential target for the treatment of rheumatoid arthritis. To explore the impact of CCR1 blockade in experimental arthritis and the underlying mechanisms, we used J-113863, a non-peptide antagonist of the mouse receptor.

Experimental Approach: Compound J-113863 was tested in collagen-induced arthritis (CIA) and three models of acute inflammation; Staphylococcus enterotoxin B (SEB)-induced interleukin-2 (IL-2), delayed-type hypersensitivity (DTH) response, and lipopolysaccharide (LPS)-induced tumour necrosis factoralpha (TNFalpha) production. In the LPS model, CCR1 knockout, adrenalectomised, or IL-10-depleted mice were also used. Production of TNFalpha by mouse macrophages and human synovial membrane samples in vitro were also studied.

Key Results: Treatment of arthritic mice with J-113863 improved paw inflammation and joint damage, and dramatically decreased cell infiltration into joints. The compound did not inhibit IL-2 or DTH, but reduced plasma TNFalpha levels in LPS-treated mice. Surprisingly, CCR1 knockout mice produced more TNFalpha than controls in response to LPS, and J-113863 decreased TNFalpha also in CCR1 null mice, indicating that its effect was unrelated to CCR1. Adrenalectomy or neutralisation of IL-10 did not prevent inhibition of TNFalpha production by J-113863. The compound did not inhibit mouse TNFalpha in vitro, but did induce a trend towards increased TNFalpha release in cells from synovial membranes of rheumatoid arthritis patients.

Conclusions And Implications: CCR1 blockade improves the development of CIA, probably via inhibition of inflammatory cell recruitment. However, results from both CCR1-deficient mice and human synovial membranes suggest that, in some experimental settings, blocking CCR1 could enhance TNF production.

Citing Articles

CXCL4 deficiency limits M4 macrophage infiltration and attenuates hyperoxia-induced lung injury.

Yu B, Jia S, Chen Y, Guan R, Chen S, Tang W Mol Med. 2024; 30(1):253.

PMID: 39707183 PMC: 11660834. DOI: 10.1186/s10020-024-01043-y.

Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1.

Toy L, Huber M, Lee M, Bartolome A, Ortiz Zacarias N, Nasser S ACS Pharmacol Transl Sci. 2024; 7(7):2080-2092.

PMID: 39022357 PMC: 11249626. DOI: 10.1021/acsptsci.4c00182.

Integrating single cell expression quantitative trait loci summary statistics to understand complex trait risk genes.

Wang L, Khunsriraksakul C, Markus H, Chen D, Zhang F, Chen F Nat Commun. 2024; 15(1):4260.

PMID: 38769300 PMC: 11519974. DOI: 10.1038/s41467-024-48143-1.

Research progress of the chemokine/chemokine receptor axes in the oncobiology of multiple myeloma (MM).

Du J, Lin Z, Fu X, Gu X, Lu G, Hou J Cell Commun Signal. 2024; 22(1):177.

PMID: 38475811 PMC: 10935833. DOI: 10.1186/s12964-024-01544-7.

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain.

Pawlik K, Mika J Molecules. 2023; 28(15).

PMID: 37570736 PMC: 10421203. DOI: 10.3390/molecules28155766.

References

Proudfoot A, Buser R, Borlat F, Alouani S, Soler D, Offord R . Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors. J Biol Chem. 1999; 274(45):32478-85. DOI: 10.1074/jbc.274.45.32478. View

Gladue R, Tylaska L, Brissette W, Lira P, Kath J, Poss C . CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. J Biol Chem. 2003; 278(42):40473-80. DOI: 10.1074/jbc.M306875200. View

Gao W, Topham P, King J, Smiley S, Csizmadia V, Lu B . Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection. J Clin Invest. 2000; 105(1):35-44. PMC: 382589. DOI: 10.1172/JCI8126. View

Tokuda A, Itakura M, Onai N, Kimura H, Kuriyama T, Matsushima K . Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice. J Immunol. 2000; 164(5):2745-51. DOI: 10.4049/jimmunol.164.5.2745. View

Liang M, Rosser M, Ng H, May K, Bauman J, Islam I . Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor. Eur J Pharmacol. 2000; 389(1):41-9. DOI: 10.1016/s0014-2999(99)00863-8. View

Murphy P, Baggiolini M, Charo I, Hebert C, Horuk R, Matsushima K . International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000; 52(1):145-76. View

Lee S, Brummet M, Shahabuddin S, Woodworth T, Georas S, Leiferman K . Cutaneous injection of human subjects with macrophage inflammatory protein-1 alpha induces significant recruitment of neutrophils and monocytes. J Immunol. 2000; 164(6):3392-401. DOI: 10.4049/jimmunol.164.6.3392. View

Liang M, Mallari C, Rosser M, Ng H, May K, Monahan S . Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem. 2000; 275(25):19000-8. DOI: 10.1074/jbc.M001222200. View

Blease K, Mehrad B, Standiford T, Lukacs N, Kunkel S, Chensue S . Airway remodeling is absent in CCR1-/- mice during chronic fungal allergic airway disease. J Immunol. 2000; 165(3):1564-72. DOI: 10.4049/jimmunol.165.3.1564. View

10.

Youssef S, Maor G, Wildbaum G, Grabie N, Karin N . C-C chemokine-encoding DNA vaccines enhance breakdown of tolerance to their gene products and treat ongoing adjuvant arthritis. J Clin Invest. 2000; 106(3):361-71. PMC: 314324. DOI: 10.1172/JCI9109. View

11.

Rottman J, Slavin A, Silva R, Weiner H, Gerard C, Hancock W . Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol. 2000; 30(8):2372-7. DOI: 10.1002/1521-4141(2000)30:8<2372::AID-IMMU2372>3.0.CO;2-D. View

12.

Sabroe I, Peck M, Van Keulen B, Jorritsma A, Simmons G, Clapham P . A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem. 2000; 275(34):25985-92. DOI: 10.1074/jbc.M908864199. View

13.

Clemetson K, Clemetson J, Proudfoot A, Power C, Baggiolini M, Wells T . Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood. 2000; 96(13):4046-54. View

14.

Lawlor K, Campbell I, ODonnell K, Wu L, Wicks I . Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis. Arthritis Rheum. 2001; 44(2):442-50. DOI: 10.1002/1529-0131(200102)44:2<442::AID-ANR63>3.0.CO;2-M. View

15.

Naya A, Sagara Y, Ohwaki K, Saeki T, Ichikawa D, Iwasawa Y . Design, synthesis, and discovery of a novel CCR1 antagonist. J Med Chem. 2001; 44(9):1429-35. DOI: 10.1021/jm0004244. View

16.

Katschke Jr K, Rottman J, Ruth J, Qin S, Wu L, Larosa G . Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum. 2001; 44(5):1022-32. DOI: 10.1002/1529-0131(200105)44:5<1022::AID-ANR181>3.0.CO;2-N. View

17.

Horuk R, Clayberger C, Krensky A, Wang Z, Grone H, Weber C . A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J Biol Chem. 2000; 276(6):4199-204. DOI: 10.1074/jbc.M007457200. View

18.

Godessart N, Kunkel S . Chemokines in autoimmune disease. Curr Opin Immunol. 2001; 13(6):670-5. DOI: 10.1016/s0952-7915(01)00277-1. View

19.

Anders H, Vielhauer V, Frink M, Linde Y, Cohen C, Blattner S . A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest. 2002; 109(2):251-9. PMC: 150841. DOI: 10.1172/JCI14040. View

20.

Branger J, van den Blink B, Weijer S, Madwed J, Bos C, Gupta A . Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol. 2002; 168(8):4070-7. DOI: 10.4049/jimmunol.168.8.4070. View