title: Hepatic granulomas induced by Schistosoma mansoni in mice deficient for connexin 43 present lower cell proliferation and higher collagen content.
abstract: Granuloma formation involves a coordinated interaction between monocytes and macrophages, epithelioid cells, lymphocytes, eosinophils, neutrophils and fibroblasts. It has been established that extracellular communication via cytokines is important for the assembly of granulomas. However, the importance of gap junctions and intercellular communication to granuloma formation and development had never been assessed. Connexins are proteins that form gap junctions, and connexin 43 (Cx43) is present in macrophages, lymphoid cells, myelogenous cells, fibroblasts and others. We analyzed the effect of heterologous deletion of Gja1 (Cx43 gene) on the formation and development of hepatic granulomas induced by Schistosoma mansoni eggs. Heterozygous (Cx43(+/-)) and wild-type (Cx43(+/+)) mice were infected subcutaneously with S. mansoni cercarie and evaluated after 6, 8 and 12 weeks. Granuloma cells express Cx43, as revealed by real-time PCR in isolated granulomas, and by immunohistochemistry. Cx43 expression was reduced in Cx43(+/-) mice, as expected. No differences in the average area of granulomas or number of cells per granuloma were observed between mice of different genotypes. However, granuloma cells from Cx43(+/-) mice displayed a reduced index of the proliferating cell nuclear antigen (PCNA) labeling at 8 and 12 weeks post-infection. Moreover, Cx43(+/-) granulomas unexpectedly presented a higher degree of fibrosis, quantified by morphometric analysis in Sirius Red-stained slides. Our results indicate that the deletion of one allele of the Cx43 gene, and possibly the reduced gap junction intercellular communication capacity (GJIC), may impair the interactions between granuloma cells, reducing their proliferation and increasing their collagen content, thereby modifying the characteristics of S. mansoni granuloma in mice.
authors.affiliation: Laboratory of Experimental Oncology, Department of Pathology, School of Veterinary Medicine, University of São Paulo, Brazil.
authors.forename: Silvia Catarina Salgado
authors.initials: SC
authors.lastname: Oloris
authors.forename: Marc
authors.initials: M
authors.lastname: Mesnil
authors.forename: Viviane Neri de Souza
authors.initials: VN
authors.lastname: Reis
authors.forename: Mônica
authors.initials: M
authors.lastname: Sakai
authors.forename: Patrícia
authors.initials: P
authors.lastname: Matsuzaki
authors.forename: Evelise de Souza Monteiro
authors.initials: Ede S
authors.lastname: Fonseca
authors.forename: Tereza Cristina
authors.initials: TC
authors.lastname: da Silva
authors.forename: José Luís
authors.initials: JL
authors.lastname: Avanzo
authors.forename: Idércio Luiz
authors.initials: IL
authors.lastname: Sinhorini
authors.forename: José Luiz
authors.initials: JL
authors.lastname: Guerra
authors.forename: Frederico Azevedo
authors.initials: FA
authors.lastname: Costa-Pinto
authors.forename: Paulo Cesar
authors.initials: PC
authors.lastname: Maiorka
authors.forename: Maria Lúcia Zaidan
authors.initials: ML
authors.lastname: Dagli
mesh_terms: D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism*; D018031:Connexin 43 / Q000172:deficiency*; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D020868:Gene Silencing; D006099:Granuloma / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000502:physiology*; D012555:Schistosomiasis mansoni / Q000378:metabolism / Q000473:pathology*
chemical_list: D018031:Connexin 43; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D003094:Collagen