title: Myocardial chemokine expression and intensity of myocarditis in Chagas cardiomyopathy are controlled by polymorphisms in CXCL9 and CXCL10.
abstract: BACKGROUND
  Chronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium.
  
  
  RESULTS
  Using confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2-6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes.
  
  
  CONCLUSIONS
  Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC.
authors.affiliation: Laboratory of Immunology, Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Luciana Gabriel
authors.initials: LG
authors.lastname: Nogueira
authors.forename: Ronaldo Honorato Barros
authors.initials: RH
authors.lastname: Santos
authors.forename: Barbara Maria
authors.initials: BM
authors.lastname: Ianni
authors.forename: Alfredo Inácio
authors.initials: AI
authors.lastname: Fiorelli
authors.forename: Eliane Conti
authors.initials: EC
authors.lastname: Mairena
authors.forename: Luiz Alberto
authors.initials: LA
authors.lastname: Benvenuti
authors.forename: Amanda
authors.initials: A
authors.lastname: Frade
authors.forename: Eduardo
authors.initials: E
authors.lastname: Donadi
authors.forename: Fabrício
authors.initials: F
authors.lastname: Dias
authors.forename: Bruno
authors.initials: B
authors.lastname: Saba
authors.forename: Hui-Tzu Lin
authors.initials: HT
authors.lastname: Wang
authors.forename: Abilio
authors.initials: A
authors.lastname: Fragata
authors.forename: Marcelo
authors.initials: M
authors.lastname: Sampaio
authors.forename: Mario Hiroyuki
authors.initials: MH
authors.lastname: Hirata
authors.forename: Paula
authors.initials: P
authors.lastname: Buck
authors.forename: Charles
authors.initials: C
authors.lastname: Mady
authors.forename: Edimar Alcides
authors.initials: EA
authors.lastname: Bocchi
authors.forename: Noedir Antonio
authors.initials: NA
authors.lastname: Stolf
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.forename: Edecio
authors.initials: E
authors.lastname: Cunha-Neto
mesh_terms: D000293:Adolescent; D000328:Adult; D002598:Chagas Cardiomyopathy / Q000235:genetics* / Q000473:pathology*; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics; D054370:Chemokine CXCL9 / Q000096:biosynthesis* / Q000235:genetics; D060467:Disease Resistance; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014349:Trypanosoma cruzi / Q000472:pathogenicity*; D055815:Young Adult
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9