title: TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-alpha blockade.
abstract: In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-alpha) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-alpha levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-alpha, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-alpha+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-alpha treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-alpha-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-alpha treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.
authors.affiliation: Laboratório de Auto-Imunidade e Imuno-Regulação, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, Brasil.
authors.forename: Karina
authors.initials: K
authors.lastname: Kroll-Palhares
authors.forename: Jaline Coutinho
authors.initials: JC
authors.lastname: Silvério
authors.forename: Andrea Alice da
authors.initials: AA
authors.lastname: Silva
authors.forename: Vladimir
authors.initials: V
authors.lastname: Michailowsky
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Marino
authors.forename: Neide Maria
authors.initials: NM
authors.lastname: Silva
authors.forename: Cristiano Marcelo Espinola
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Luzia Maria de Oliveira
authors.initials: LM
authors.lastname: Pinto
authors.forename: Ricardo Tostes
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: Joseli
authors.initials: J
authors.lastname: Lannes-Vieira
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D002598:Chagas Cardiomyopathy / Q000188:drug therapy / Q000276:immunology*; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D000069285:Infliximab; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019713:Receptors, CCR5 / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D019713:Receptors, CCR5; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab