Regulation of inflammation during Pseudomonas aeruginosa lung infection

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that is a common cause of nosocomial infections in immunocompromised individuals. The healthy individuals effectively clear P. aeruginosa infections through tightly controlled inflammatory responses. Dysregulated inflammation increases host susceptibility to P. aeruginosa infections and causes severe lung damage. The molecular mechanisms governing the inflammatory responses to P. aeruginosa infections remain incompletely defined. Herein, I identified a novel role of regulator of calcineurin-1 (RCAN1) in P. aeruginosa lipopolysaccharide (LPS)-activated TLR4 signaling, and a detrimental role of early growth response 1 (Egr-1) in host defense against P. aeruginosa lung infection. RCAN1, a small evolutionarily conserved protein that inhibits calcineurin phosphatase activity, functions as a negative regulator of inflammation. I found that RCAN1 downregulates myeloid differentiation primary response 88 (MyD88)-NF-κB pathway through inhibition of IκBα phosphorylation, and promotes activation of TIR-domain-containing adapter-inducing interferon-β (TRIF)-interferon-stimulated response element (ISRE) pathway through regulation of IRF7 activation and expression. Egr-1 is a zinc-finger transcription factor that controls inflammatory responses. I demonstrated that Egr-1 promotes inflammation associated with increased mortality, and negatively regulates nitric oxide production for bacterial clearance during P. aeruginosa lung infection. Together, these findings improve our understanding of regulatory mechanisms involved in host defense against P. aeruginosa infections in innate immunity, and suggest that RCAN1 and Egr-1 could be potential therapeutic targets to enhance bacterial clearance or reduce the risk of systemic inflammation.