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

TitleHepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function.
Publication TypeJournal Article
Year of Publication2010
AuthorsSander, LE, Sackett, SDutton, Dierssen, U, Beraza, N, Linke, RP, Müller, M, J Blander, M, Tacke, F, Trautwein, C
JournalJ Exp Med
Volume207
Issue7
Pagination1453-64
Date Published2010 Jul 05
ISSN1540-9538
KeywordsAcute-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, Sepsis, Serum Amyloid A Protein, Signal Transduction, Spleen, STAT3 Transcription Factor
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.

DOI10.1084/jem.20091474
Alternate JournalJ. Exp. Med.
PubMed ID20530204
PubMed Central IDPMC2901069