Role of the MIF homologue D-dopachrome tautomerase (D-DT) in sepsis

• Applicant: Dr. Wibke Karin Schulte
• Subject Area: Pneumology, Thoracic Surgery ; Cell Biology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 227721277

Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Studies on their pathophysiology have revealed an imbalance in the inflammatory network leading to tissue damage, organ failure and ultimately death. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and a pivotal regulator of the immune response implicated in the pathogenesis of various acute and chronic inflammatory diseases. Numerous studies have linked MIF to sepsis pathology. On a molecular level, MIF shares structural homology with the protein D-dopachrome tautomerase (D-DT). To date, reports on the functions of D-DT remain extremely limited. My research group and I recently identified D-DT as a MIF-like cytokine with an overlapping spectrum of activities, and provided first evidence for an involvement of D-DT in sepsis. The overall objective of this project is to conduct detailed functional studies on the role of D-DT in sepsis by means of the newly generated D-dt-knockout and Mif-/D-dt-double knockout mice. In vitro and in vivo studies will focus on the role of D-DT in acute inflammation triggered by lipopolysaccharide, the main virulence factor of gram-negative bacteria, and in polymicrobial sepsis induced by the surgical procedure cecal ligation and puncture. Subsequently, I intend to study whether D-DT mediates the inflammatory response against various bacteria. As anti-MIF treatments were shown to be beneficial in many inflammatory diseases and are currently advancing towards clinical application, knowing about the activity of a second MIF-like protein, namely D-DT, is essential to understand the potential therapeutic actions of MIF inhibitors in clinical settings, and to improve the clinical outcome of sepsis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Richard Bucala, Ph.D.