Role of the MIF homologue D-dopachrome tautomerase (D-DT) in sepsis
Cell Biology
Final Report Abstract
Sepsis, or the invasion of microbial pathogens into the bloodstream, is a leading cause of death in intensive care units. Numerous studies of sepsis pathophysiology have revealed a dysregulated immune responses leading to tissue damage, organ failure and ultimately, death. Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that has been studied extensively in vitro, in vivo, and in human genetic studies of sepsis. Recently, we cloned a second novel MIF-like protein in the human genome, called D-dopachrome tautomerase (D-DT or MIF-2), which shows striking structural similarity with MIF. We found that D-DT regulates macrophage activation responses and is produced in elevated levels in patients with sepsis. We now have developed a Ddt/- mouse strain and have investigated the specific role of D-DT in sepsis. Our studies in the cecal ligation and puncture (CLP) polymicrobial sepsis model revealed that MIF and D-DT levels are elevated at the local site of infection and in the systemic circulation. Importantly, we observed a survival difference between Mif/- and Ddt/- mice in sepsis with evidence that MIF and D-DT differentially recruit distinct macrophage subsets to the site of peritoneal infection. The improved survival of Mif/- mice was associated with reduced numbers of a novel population of proinflammatory small peritoneal macrophages (SPMs) that, unlike resident large peritoneal macrophages (LPMs), is recruited to the peritoneal cavity following CLP. In contrast, deletion of Ddt resulted in higher numbers of SPMs, which did not protect from lethal sepsis. The adoptive transfer of SPMs increases the lethality of sepsis. We have now started to characterize SPMs and LPMs via RNAseq with a special focus on functional responses that mediate deleterious inflammation in order to determine how MIF and D-DT selectively regulate these macrophage subsets. Such knowledge will be crucial for a better understanding of pathophysiologic mechanisms in sepsis and the development of more effective therapies.
Publications
- 2013. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets - an updated view. Mediators Inflamm 2013:165974
Schulte W, Bernhagen J, Bucala R
(See online at https://doi.org/10.1155/2013/165974) - 2015. Interaction of MIF family proteins in myocardial ischemia/reperfusion damage and their influence on clinical outcome of cardiac surgery patients. Antioxid Redox Signal 23(11):865-79
Stoppe C, Rex S, Goetzenich A, Kraemer S, Emontzpohl C, Soppert J, Averdunk L, Sun Y, Rossaint R, Lue H, Huang C, Song Y, Pantouris G, Lolis E, Leng L, Schulte W, Bucala R, Weber C, Bernhagen J
(See online at https://doi.org/10.1089/ars.2014.6243) - 2015. Operative Management of Hilar Renal Artery Aneurysm in a Pregnant Patient. Ann Vas Dis 8(3):242-5
Schulte W, Rodriguez-Davalos M, Lujic M, Schlosser F, Sumpio B
(See online at https://doi.org/10.3400/avd.cr.15-00026) - The clinical significance of the MIF homolog d-dopachrome tautomerase (MIF-2) and its circulating receptor (sCD74) in burn. Burns Volume 42, Issue 6, September 2016, Pages 1265-1276
Kim BS, Stoppe C, Boecker A, Ling L, Sauler M, Assis D, Schulte W, Picychna M, Simons D, Hager S, Bernhagen J, Bucala R, Grieb G, Pallua N
(See online at https://doi.org/10.1016/j.burns.2016.02.005)
