The Peroxisome Proliferator-Activated Receptor alpha- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

Abstract

Peroxisome proliferator-activated receptor alpha (PPAR alpha) shows promising potential to enhance host defenses against Mycobacterium tuberculosis infection. Herein we evaluated the protective effect of PPAR alpha against nontuberculous mycobacterial (NTM) infections. Using a rapidly growing NTM species, Mycobacterium abscessus (Mabc), we found that the intracellular bacterial load and histopathological damage were increased in PPAR alpha-null mice in vivo. In addition, PPAR alpha deficiency led to excessive production of proinflammatory cytokines and chemokines after infection of the lung and macrophages. Notably, administration of gemfibrozil (GEM), a PPAR alpha activator, significantly reduced the in vivo Mabc load and inflammatory response in mice. Transcription factor EB was required for the antimicrobial response against Mabc infection. Collectively, these results suggest that manipulation of PPAR alpha activation has promising potential as a therapeutic strategy for NTM disease.