Novel proresolving and tissue-regenerative resolvin and protectin sulfido-conjugated pathways

FASEB J. 2015 May;29(5):2120-36. doi: 10.1096/fj.14-268441. Epub 2015 Feb 20.

Abstract

Local mediators orchestrate the host response to both sterile and infectious challenge and resolution. Recent evidence demonstrates that maresin sulfido-conjugates actively resolve acute inflammation and promote tissue regeneration. In this report, we investigated self-limited infectious exudates for novel bioactive chemical signals in tissue regeneration and resolution. By use of spleens from Escherichia coli infected mice, self-resolving infectious exudates, human spleens, and blood from patients with sepsis, we identified 2 new families of potent molecules. Characterization of their physical properties and isotope tracking demonstrated that the bioactive structures contained a docosahexaenoate backbone and sulfido-conjugated triene or tetraene double-bond systems. Activated human phagocytes converted 17-hydro(peroxy)-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid to these bioactive molecules. Regeneration of injured planaria was accelerated with nanomolar amounts of 16-glutathionyl, 17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid and 16-cysteinylglycinyl, 17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid (Protectin sulfido-conjugates) or 8-glutathionyl, 7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid and 8-cysteinylglycinyl, 7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid (Resolvin sulfido-conjugates). Each protectin and resolvin sulfido-conjugate dose dependently (0.1-10 nM) stimulated human macrophage bacterial phagocytosis, phagolysosomal acidification, and efferocytosis. Together, these results identify 2 novel pathways and provide evidence for structural elucidation of new resolution moduli. These resolvin and protectin conjugates identified in mice and human infected tissues control host responses promoting catabasis.

Keywords: infection; inflammation; leukocytes; resolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • CD59 Antigens / chemistry*
  • Cells, Cultured
  • Chromatography, Liquid
  • Docosahexaenoic Acids / chemistry*
  • Escherichia coli / drug effects
  • Escherichia coli Infections / drug therapy
  • Escherichia coli Infections / microbiology
  • Escherichia coli Infections / pathology
  • Humans
  • Inflammation / drug therapy
  • Inflammation Mediators / metabolism
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Peritonitis / drug therapy
  • Peritonitis / microbiology
  • Peritonitis / pathology
  • Phagocytosis / drug effects*
  • Planarians / cytology
  • Planarians / drug effects*
  • Regeneration / drug effects*
  • Regeneration / physiology
  • Sepsis / drug therapy
  • Sepsis / microbiology
  • Sepsis / pathology
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / metabolism
  • Tandem Mass Spectrometry

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • CD59 Antigens
  • Inflammation Mediators
  • resolvin D1
  • Docosahexaenoic Acids