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Status |
Public on May 27, 2010 |
Title |
Hepatic acute phase proteins control innate immune responses during infection by promoting myeloid derived suppressor cell function |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
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 anti-inflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a murine model for polymicrobial sepsis we show here that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6-family cytokines, dramatically increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through signal transducer and activator of transcription (Stat)3 was required to control systemic inflammation. Notably, hepatic gp130/Stat3 activation was also a prerequisite to facilitate mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for anti-inflammatory properties in cancer. We show that MDSCs were critical to regulate innate inflammation and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. We identified serum amyloid A and Cxcl-1/KC as hepatic acute phase genes that cooperatively promoted MDSC mobilization, accumulation and survival. Administration of these proteins efficiently elevated MDSC numbers and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through acute phase proteins critically controls inflammatory responses during infection.
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Overall design |
Control [gp130f/f] and liver-specific Gp130 knockout [gp130delta(hepa)] mice were subjected to polymicrobial sepsis. Twelve hours after induction of sepsis mice were sacrificed and livers were removed. For control treatment mice were sacrified without any prior treatment. Total RNA was isolated and subjected to gene expression profiling.
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Contributor(s) |
Sander LE, Dutton Sackett S, Dierssen U, Beraza N, Linke RP, Müller M, Magarian Blander J, Tacke F, Trautwein C |
Citation(s) |
20530204 |
Submission date |
May 26, 2010 |
Last update date |
Feb 11, 2019 |
Contact name |
Guido Hooiveld |
E-mail(s) |
guido.hooiveld@wur.nl
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Organization name |
Wageningen University
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Department |
Div. Human Nutrition & Health
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Lab |
Nutrition, Metabolism & Genomics Group
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Street address |
HELIX, Stippeneng 4
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City |
Wageningen |
ZIP/Postal code |
NL-6708WE |
Country |
Netherlands |
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Platforms (1) |
GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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Samples (12)
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Relations |
BioProject |
PRJNA127473 |