Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function.
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.
Department of Medicine III, RWTH University Hospital, 52074 Aachen, Germany. leif.sander@mssm.edu
Leif E
LE
Sander
Sara Dutton
SD
Sackett
Uta
U
Dierssen
Naiara
N
Beraza
Reinhold P
RP
Linke
Michael
M
Müller
J Magarian
JM
Blander
Frank
F
Tacke
Christian
C
Trautwein
D000209:Acute-Phase Proteins / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001419:Bacteria / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000517:prevention & control; D008099:Liver / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology
D000209:Acute-Phase Proteins; D039481:CD11b Antigen; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130