PPARγ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model

We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease which bears similarities to human sarcoidosis pathology including alveolar macrophage deficiency of peroxisome-proliferator-activated receptor gamma (PPARγ). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial Early Secreted Antigenic Target Protein 6 (ESAT-6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNT with or without ESAT-6 peptide-14 were instilled by oropharyngeal route into macrophage-specific PPARγ KO or wild-type mice. Controls received PBS or ESAT-6. Lung tissues, bronchoalveolar lavage (BAL) cells and fluid, were evaluated 60 days post instillation. PPARγ-KO mice receiving MWCNT+ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) vs wild-type mice or PPARγ-KO mice receiving only MWCNT. Immunostaining of lung tissues noted elevated fibronectin and Sig...