THE PROTEIN PROHIBITIN DISPLAYS SYSTEMIC ANTI-INFLAMMATORY AND ORGAN-PROTECTIVE EFFECTS DURING SEPSIS
Christine Psaltis, East Carolina University
Christine Psaltis1, Brita Kilburg-Basnyat1, Taylor Mattox1, Kathleen Thayne1, Jim Aloor1, Jacques Robidoux1, Ethan Anderson2*, Kymberly Gowdy1*
1. Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC
2. Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa
*Authors contributed equally
Background: Sepsis, a systemic inflammatory response to infection, is a leading cause of mortality worldwide. Maintaining organ function during sepsis is critical to improve patient outcomes. Prohibitin (PHB), a ubiquitous protein, has multiple roles in mitochondrial structure, metabolism, and cell death. However, PHB’s role in sepsis has been unexplored.
Methods: Using in vivo sepsis model, we injected C57Bl/6J mice i.p. with lipopolysaccharide (LPS). Following LPS, mice were given recombinant prohibitin (rPHB) i.p. Organs were analyzed for injury and inflammation. Cardiac function was measured via echocardiogram. Blood was used for systemic immune cell characterization by flow cytometry. HL1 cardiomyocytes overexpressing PHB exposed to TNF-α/IL-1β were used to measure mitochondrial function and pro-inflammatory cytokines.
Results: Systemic LPS decreased cardiac function but increased blood neutrophils (PMNs) (CD45+Ly6G+) and PMN expression of CD11b. However, rPHB restored LPS decreases in cardiac contractility and decreased CD11b expression. TNF-α/IL-1β increased pro-inflammatory cytokine expression and decreased mitochondrial function. However, when cardiomyocytes over-expressed PHB were incubated with TNF-α/IL-1β, mitochondrial dysfunction and increased proinflammatory cytokine expression were mitigated.
Conclusions: We found that PHB decreases systemic inflammation, decreases neutrophil maturation/recruitment and restores cardiac contractility during sepsis. PHB significantly improves mitochondrial function in cardiomyocytes. These findings illustrate PHB’s diverse roles in enhancing mitochondrial function and regulating innate immunity.