The hepatic acute phase response controls inflammation during sepsis by promoting myeloid suppressor cell functions

Sepsis is a major cause of mortality worldwide characterized by a dysregulated inflammatory response to infection. Patients with chronic liver diseases have significantly increased risk of acquiring sepsis and and show a higher sepsis related mortality. The underlying mechanisms are only partially understood. The liver is the major source of acute phase proteins (APPs) which are regarded as important components of the innate immune response. However, due to the large diversity of APPs with pro- and anti-inflammatory functions, their overall role in infections is not well defined. Here we show that a critical regulator of the hepatic acute phase response (APR) is the signal transducer and activator of transcription (STAT) 1/3 pathway downstream of the common interleukin-6 (IL-6) family cytokine receptor gp130. Using a murine model for polymicrobial sepsis, we show that hepatocyte-specific deficiency in gp130 (gp130Δhepa) or gp130-STAT1/3 signaling (gp130StatΔhepa) resulted in enhanced mortality despite normal bacterial clearance and inflammation. Surprisingly, gp130Δhepa mice failed to downmodulate the inflammatory response. This was associated with a lack of myeloid derived suppressor cell (MDSC) accumulation in the spleen, a population of cells known mainly for its immunosuppressive functions in cancer. MDSCs were critical for inhibiting inflammatory cytokine secretion, and their adoptive transfer protected gp130Δhepa mice from sepsis associated mortality. Administration of the APP serum amyloid A (SAA) and the chemokine KC, both strongly upregulated in sepsis in the livers of control but not gp130Δhepa mice, reversed the detrimental effects of gp130 deficiency and restored mobilization, survival and splenic accumulation of MDSCs. Our results demonstrate that the hepatic APR plays an important negative regulatory role during innate immunity to infection mediated through a novel gp130-dependent pathway of mobilizing immunosuppressive MDSCs.

Acute phase response - myeloid derived suppressor cells