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.

[1]  M. Manns,et al.  The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. , 2005, The Journal of clinical investigation.

[2]  R. Medzhitov Recognition of microorganisms and activation of the immune response , 2007, Nature.

[3]  J. Raynes,et al.  Serum amyloid A is an innate immune opsonin for Gram-negative bacteria. , 2006, Blood.

[4]  J. Filep,et al.  Prevention of In vitro neutrophil adhesion to endothelial cells through shedding of L-selectin by C-reactive protein and peptides derived from C-reactive protein. , 1997, The Journal of clinical investigation.

[5]  M. Manns,et al.  Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration* , 2003, The Journal of Biological Chemistry.

[6]  K. Tracey,et al.  Experimental Therapeutic Strategies for Severe Sepsis , 2008, Annals of the New York Academy of Sciences.

[7]  Hong Tang,et al.  Adaptive immune cells temper initial innate responses , 2007, Nature Medicine.

[8]  J. Bylund,et al.  Serum amyloid A inhibits apoptosis of human neutrophils via a P2X7‐sensitive pathway independent of formyl peptide receptor‐like 1 , 2008, Journal of leukocyte biology.

[9]  R. Jove,et al.  Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer , 2004, The Journal of Immunology.

[10]  OLAND,et al.  TREATMENT OF SEPTIC SHOCK WITH THE TUMOR NECROSIS FACTOR RECEPTOR : Fc FUSION PROTEIN C , 2000 .

[11]  D. Rittirsch,et al.  Immunodesign of experimental sepsis by cecal ligation and puncture , 2008, Nature Protocols.

[12]  R. Hotchkiss,et al.  Apoptosis and caspases regulate death and inflammation in sepsis , 2006, Nature Reviews Immunology.

[13]  D. Carbone,et al.  Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. , 2008, Cancer cell.

[14]  L. F. Kolakowski,et al.  Expression and biologic characterization of the murine chemokine KC. , 1995, Journal of immunology.

[15]  G. Matuschak Lung-liver interactions in sepsis and multiple organ failure syndrome. , 1996, Clinics in chest medicine.

[16]  D. Mannino,et al.  Cirrhosis as a risk factor for sepsis and death: analysis of the National Hospital Discharge Survey. , 2003, Chest.

[17]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[18]  M. Sitkovsky,et al.  Model organisms: Animal Models of sepsis: setting the stage , 2005, Nature Reviews Drug Discovery.

[19]  W. Nacken,et al.  Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein , 2008, The Journal of experimental medicine.

[20]  Peter A. Ward,et al.  Harmful molecular mechanisms in sepsis , 2008, Nature Reviews Immunology.

[21]  B. Jenkins,et al.  Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice , 2002, Nature Medicine.

[22]  K. Rajewsky,et al.  Postnatally Induced Inactivation of gp130 in Mice Results in Neurological, Cardiac, Hematopoietic, Immunological, Hepatic, and Pulmonary Defects , 1998, The Journal of experimental medicine.

[23]  E. Dupont,et al.  Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients. , 1993, Gastroenterology.

[24]  M. Manns,et al.  Lack of gp130 expression in hepatocytes promotes liver injury. , 2003, Gastroenterology.

[25]  S. Albelda,et al.  Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response1 , 2007, The Journal of Immunology.

[26]  M. Manns,et al.  Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. , 2008, Gastroenterology.

[27]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[28]  M. Manns,et al.  A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. , 2008, Gastroenterology.

[29]  R. Ye,et al.  Cutting Edge: TLR2 Is a Functional Receptor for Acute-Phase Serum Amyloid A1 , 2008, The Journal of Immunology.

[30]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[31]  V. Kuchroo,et al.  CD11b+Ly-6Chi Suppressive Monocytes in Experimental Autoimmune Encephalomyelitis1 , 2007, The Journal of Immunology.

[32]  R. Hotchkiss,et al.  The pathophysiology and treatment of sepsis. , 2003, The New England journal of medicine.

[33]  D. Ritchie,et al.  HEPATOCYTE‐STIMULATING FACTOR: A MONOCYTE‐DERIVED ACUTE‐PHASE REGULATORY PROTEIN , 1983, Annals of the New York Academy of Sciences.

[34]  L. Moldawer,et al.  MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis , 2007, The Journal of experimental medicine.

[35]  K. Yasukawa,et al.  IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. , 1993, Science.

[36]  R. Badolato,et al.  Serum amyloid A is a chemoattractant: induction of migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes , 1994, The Journal of experimental medicine.

[37]  E. Dupont,et al.  Tumor necrosis factor α and interleukin 6 plasma levels in infected cirrhotic patients , 1993 .

[38]  C. Trautwein,et al.  Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man , 2007, The Journal of experimental medicine.

[39]  P. De Baetselier,et al.  Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. , 2008, Blood.

[40]  K. Gupta,et al.  Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer , 2007, Nature Medicine.

[41]  V. Kuchroo,et al.  CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. , 2007, Journal of immunology.

[42]  M. Young,et al.  Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. , 1987, Cancer research.

[43]  Peter A. Ward,et al.  Novel strategies for the treatment of sepsis , 2003, Nature Medicine.

[44]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[45]  S. Imbeaud,et al.  Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours , 2009, Nature.

[46]  W. Alexander,et al.  Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation , 2001, The Journal of experimental medicine.

[47]  R. Zinkernagel,et al.  Impaired immune and acute-phase responses in interleukin-6-deficient mice , 1994, Nature.

[48]  S. Opal,et al.  Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. , 1996, The New England journal of medicine.