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The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.

ABSTRACT: The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-? signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-?-dependent vascular remodeling.Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed.Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-? activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation.Combined IL-4 and IL-13 deficiency is required for protection against TGF-?-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.

SUBMITTER: Kumar R

PROVIDER: S-EPMC4642207 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.

Kumar Rahul R Mickael Claudia C Chabon Jacob J Gebreab Liya L Rutebemberwa Alleluiah A Garcia Alexandra Rodriguez AR Koyanagi Daniel E DE Sanders Linda L Gandjeva Aneta A Kearns Mark T MT Barthel Lea L Janssen William J WJ Mauad Thais T Bandeira Angela A Schmidt Eric E Tuder Rubin M RM Graham Brian B BB

American journal of respiratory and critical care medicine 20151001 8

<h4>Rationale</h4>The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-β signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.<h4>Objectives</h4>We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-β-dep ...[more]

PMID: 26192556

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Project description:Rationale: Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease by whole-lung transcriptome analysis. Methods: Wildtype mice were experimentally exposed to S. mansoni ova by intraperitoneal sensitization followed by tail vein augmentation, and the phenotype assessed by right ventricular catheterization and tissue histology, RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, the latter analyzed using 2 bioinformatic methods. Functional testing of the candidate IL-6 pathway was determined using IL6-knockout mice and the STAT3 inhibitor STI-201. Results: Wild-type mice exposed to S. mansoni had increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole lung transcriptome analysis identified the IL6-STAT3-NFATc2 pathway as being upregulated, which was confirmed by PCR and immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL6 or treated with STI-201 developed pulmonary hypertension associated with significant intima remodeling after exposure to S. mansoni. Conclusions: Whole lung transcriptome analysis identified upregulation of the IL6-STAT3-NFATc2 pathway, and IL6 signaling was found to be protective against Schistosoma-induced intimal remodeling. Affy Mouse ST1.0 chip used. Data published in: Protective Role of IL6 in Vascular Remodeling in Schistosoma-Pulmonary Hypertension. Graham BB, Chabon J, Kumar R, Kolosionek E, Gebreab L, Debella E, Edwards M, Diener K, Shade T, Bifeng G, Bandeira A, Butrous G, Jones K, Geraci M, Tuder RM. Am J Respir Cell Mol Biol. 2013 Jul 1. [Epub ahead of print] PMID: 23815102

Dataset Information

The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.

Publications

The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.

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