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

Sander, Leif E, Sackett, Sara Dutton, Dierssen, Uta, Beraza, Naiara, Linke, Reinhold P, Müller, Michael, Blander, J Magarian, Tacke, Frank and Trautwein, Christian (2010) Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. Journal of Experimental Medicine, 207 (7). pp. 1453-1464. ISSN 0022-1007

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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.

Item Type: Article
Uncontrolled 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
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 10 Jun 2014 20:48
Last Modified: 21 Apr 2020 22:52
URI: https://ueaeprints.uea.ac.uk/id/eprint/47687
DOI: 10.1084/jem.20091474

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