Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

Leif E Sander, Sara Dutton Sackett, Uta Dierssen, Naiara Beraza, Reinhold P Linke, Michael Müller, J Magarian Blander, Frank Tacke, Christian Trautwein

Research output: Contribution to journalArticlepeer-review

247 Citations (Scopus)

Abstract

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130-STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection.
Original languageEnglish
Pages (from-to)1453-1464
Number of pages12
JournalJournal of Experimental Medicine
Volume207
Issue number7
DOIs
Publication statusPublished - 5 Jul 2010

Keywords

  • Acute-Phase Proteins
  • Animals
  • Antigens, CD11b
  • Apoptosis
  • Bacteria
  • Cell Movement
  • Chemokine CXCL1
  • Cytokine Receptor gp130
  • Gene Expression Profiling
  • Hepatocytes
  • Immunity, Innate
  • Inflammation
  • Liver
  • Male
  • Mice
  • Myeloid Cells
  • STAT3 Transcription Factor
  • Sepsis
  • Serum Amyloid A Protein
  • Signal Transduction
  • Spleen

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