Defective T-lymphocyte migration to muscles in dystrophin-deficient mice.
Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting 1 in 3500 males, is caused by mutations in the dystrophin gene. DMD leads to degeneration of skeletal and cardiac muscles and to chronic inflammation. The mdx/mdx mouse has been widely used to study DMD; this model mimics most characteristics of the disease, including low numbers of T cells in damaged muscles. In this study, we aimed to assess migration of T cells to the heart and to identify any alterations in adhesion molecules that could possibly modulate this process. In 6-week-old mdx/mdx mice, blood leukocytes, including T cells, were CD62L(+), but by 12 weeks of age down-modulation was evident, with only approximately 40% of T cells retaining this molecule. Our in vitro and in vivo results point to a P2X7-dependent shedding of CD62L (with high levels in the serum), which in 12-week-old mdx/mdx mice reduces blood T cell competence to adhere to cardiac vessels in vitro and to reach cardiac tissue in vivo, even after Trypanosoma cruzi infection, a known inducer of lymphoid myocarditis. In mdx/mdx mice treated with Brilliant Blue G, a P2X7 blocker, these blood lymphocytes retained CD62L and were capable of migrating to the heart. These results provide new insights into the mechanisms of inflammatory infiltration and immune regulation in DMD.
Laboratory for Innovations in Therapy, Teaching and Bioproducts, Oswaldo Cruz Institute-Fiocruz, Rio de Janeiro, Brazil.
Cynthia M
CM
Cascabulho
Cristiane
C
Bani Corrêa
Vinícius
V
Cotta-de-Almeida
Andrea
A
Henriques-Pons
D000818:Animals; D001808:Blood Vessels / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D016189:Dystrophin / Q000172:deficiency* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D019041:L-Selectin / Q000097:blood; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009043:Motor Activity; D009132:Muscles / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000276:immunology / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D014349:Trypanosoma cruzi / Q000502:physiology
D016189:Dystrophin; D058486:Receptors, Purinergic P2X7; D019041:L-Selectin