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
|Journal||Journal of Experimental Medicine|
|Publication status||Published - 2010|
- severe sepsis
- signal transducer
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Hepatic acute phase proteins control innate immune responses during infection by promoting myeloid derived suppressor cell function
Sander, L. E. (Creator), Dutton Sackett, S. (Creator), Dierssen, U. (Creator), Beraza, N. (Creator), Linke, R. P. (Creator), Muller, M. (Creator), Magarian Blander, J. (Creator), Tacke, F. (Creator) & Trautwein, C. (Creator), Wageningen University, 27 May 2010