title: Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis.
abstract: Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1α and β and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukocyte trafficking in models of colitis, and evaluate the therapeutic potential of maraviroc, an orally active CCR5 antagonist used in the treatment of CCR5-tropic HIV. Acute and chronic colitis were induced by administration of DSS or TNBS to wild-type and CCR5(-/-) mice or adoptive transfer of splenic naïve CD4(+) T-cells from wild type or CCR5(-/-) mice into RAG-1(-/-). CCR5 gene ablation reduced the mucosal recruitment and activation of CCR5-bearing CD4(+) and CD11b(+) leukocytes, resulting in profound attenuation of signs and symptoms of inflammation in the TNBS and transfer models of colitis. In the DSS/TNBS colitis and in the transfer model, maraviroc attenuated development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes. In summary, CCR5 regulates recruitment of blood leukocytes into the colon indicating that targeting CCR5 may offer therapeutic options in IBDs.
authors: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
authors: Andrea
authors: A
authors: Mencarelli
authors: Dipartimento di Medicina, Università di Perugia, Piazza L. Severi 1, Perugia 06132, Italy.
authors: Sabrina
authors: S
authors: Cipriani
authors: Dipartimento di Medicina, Università di Perugia, Piazza L. Severi 1, Perugia 06132, Italy.
authors: Daniela
authors: D
authors: Francisci
authors: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors: Luca
authors: L
authors: Santucci
authors: Dipartimento di Medicina, Università di Perugia, Piazza L. Severi 1, Perugia 06132, Italy.
authors: Franco
authors: F
authors: Baldelli
authors: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors: Eleonora
authors: E
authors: Distrutti
authors: Dipartimento di Scienze Chirurgiche e Biomediche, Università di Perugia, Piazza L. Severi 1, Perugia 06132, Italy.
authors: Stefano
authors: S
authors: Fiorucci
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000037:antagonists & inhibitors; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000502:physiology; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D000077592:Maraviroc; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D039481:CD11b Antigen; D018946:Chemokine CCL5; D018925:Chemokines; D003510:Cyclohexanes; D018398:Homeodomain Proteins; D014230:Triazoles; C064658:RAG-1 protein; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D000077592:Maraviroc