Peroxisome Proliferator-Activated Receptor Gamma Deficiency Promotes a T Lymphocyte Response in a Murine Model of Chronic Pulmonary Sarcoidosis

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Victoria L Sanderford (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Sarcoidosis is a chronic granulomatous disease of unknown etiology. Previous studies from our lab have shown a deficiency of the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR[gamma]) in the alveolar macrophages of sarcoidosis patients. We established a murine model of granuloma formation by instillation with multiwall carbon nanotubes (MWCNT) , and the expression of PPAR[gamma] was also decreased in MWCNT instilled mice. There is evidence linking lymphocyte reactivity to mycobacterial antigens in sarcoidosis , so we hypothesized that addition of mycobacterial peptide early secretory antigenic target 6 (ESAT-6) to MWCNT might exacerbate the murine T effector cell response. MWCNT with or without ESAT-6 peptide 14 were instilled into macrophage-specific PPAR[gamma]-KO or wild-type mice. Controls received vehicle or ESAT-6 alone. Bronchoalveolar lavage (BAL) fluid was collected for analysis via qPCR , and lymph nodes were collected for histology , qPCR , in vitro studies , or flow cytometric analysis. PPAR[gamma]-KO mice receiving MWCNT+ESAT-6 displayed markedly increased granuloma formation and exhibited mediastinal lymphadenopathy. Additionally , PPAR[gamma]-KO mice treated with MWCNT+ESAT-6 exhibited exacerbated fibrotic severity at 20- and 60- days post-instillation. Similarly , lymphocyte frequency was elevated in the BAL of PPAR[gamma]-KO mice compared to controls at 20- and 60-days post-instillation with MWCNT+ESAT-6. Further , TH17 associated transcription factor ROR[gamma]t and immune regulatory marker PD1 were elevated in PPAR[gamma]-KO mice treated with MWCNT+ESAT-6 compared to sham mice at both time points , with elevation of multiple other TH17 associated genes at 60 days post instillation. Carbon nanotubes were observed in the mediastinal lymph nodes of PPAR[gamma]-KO and wild-type mice post-instillation with MWCNT and MWCNT+ESAT-6 , and flow cytometric analyses revealed that CD4+ T cells were significantly elevated in PPAR[gamma]KO mice receiving MWCNT+ESAT-6. These findings suggest that instillation of PPAR[gamma]-KO mice with MWCNT+ESAT-6 elicits an exacerbated granulomatous and T lymphocyte mediated response.

Additional Information

Publication

Thesis

Language: English

Date: 2019

Keywords

Granuloma, Mycobacterial antigens, Carbon nanotubes

Subjects

Email this document to