Title

Peroxisome Proliferator-activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model

Authors

Anagha Malur, Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine.
Arjun Mohan, Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine.
Robert A. Barrington, Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama.
Nancy Leffler, Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine.
Amrita Malur, Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine.
Barbara Muller-Borer, Department of Engineering.
Gina Murray, Department of Pathology, and.
Kim Kew, Department of Chemistry, East Carolina University, Greenville, North Carolina.
Chuanzhen Zhou, Analytical Instrumentation Facility and.
Josh Russell, Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina; and.
Jacob L. Jones, Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina; and.
Christopher J. Wingard, Department of Physical Therapy, School of Movement and Rehabilitation Sciences, College of Health Professions, Bellarmine University, Louisville, Kentucky.
Barbara P. Barna, Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine.
Mary Jane Thomassen, Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine.

Document Type

Article

Publication Title

American journal of respiratory cell and molecular biology

Abstract

We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator-activated receptor γ (PPARγ). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPARγ-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPARγ-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARγ-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c infiltrating alveolar macrophages in the presence of MWCNT + ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-β and the TGF-β pathway mediator IL-13 in PPARγ-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARγ-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-β production, was elevated in PPARγ-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARγ-KO but not wild-type mice. These data indicate that PPARγ deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT + ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis.

First Page

198

Last Page

208

DOI

10.1165/rcmb.2018-0346OC

Publication Date

8-1-2019

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