Gut-derived commensal bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity

Abstract

Intraorgan dendritic cells (DCs) monitor the environment and help translate triggers of innate immunity into adaptive immune responses. Liver-based DCs are continually exposed, via gut-derived portal venous blood, to potential antigens and bacterial products that can trigger innate immunity. However, somehow the liver avoids a state of perpetual inflammation and protects central immune organs from overstimulation. In this study, we tested the hypothesis that hepatic interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) activity increases the activation/maturation threshold of hepatic DCs toward innate immune signals. The results show that the liver nuclear STAT3 activity is significantly higher than that of other organs and is IL-6 -dependent. Hepatic DCs in normal IL-6 wild-type (IL-6 ؉/؉ ) mice are phenotypically and functionally less mature than DCs from IL-6 -deficient (IL-6 ؊/؊ ) or STAT3-inhibited IL-6 ؉/؉ mice, as determined by surface marker expression, proinflammatory cytokine secretion, and allogeneic T-cell stimulation. IL-6 ؉/؉ liver DCs produce IL-6 in response to exposure to lipopolysaccharide (LPS) and cytidine phosphate guanosine oligonucleotides (CpG) but are resistant to maturation compared with IL-6 ؊/؊ liver DCs. Conversely, exogenous IL-6 inhibits LPS-induced IL-6 ؊/؊ liver DC maturation. IL-6/STAT3 signaling influences the liver DC expression of toll-like receptor 9 and IL-1 receptor associated kinase-M. The depletion of gut commensal bacteria in IL-6 ؉/؉ mice with oral antibiotics decreased portal blood endotoxin levels, lowered the expression of IL-6 and phospho-STAT3, and significantly increased liver DC maturation. Conclusion: Gut-derived bacterial products, by stimulating hepatic IL-6/STAT3 signaling, inhibit hepatic DC activation/maturation and thereby elevate the threshold needed for translating triggers of innate immunity into adaptive immune responses. Manipulating gut bacteria may therefore be an effective strategy for altering intrahepatic immune responses.

PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3

“…It has been demonstrated that liver DCs have reduced T-cell stimulatory capacities [47,48]. The data of Lunz et al [49] support these findings. They could show that gutderived bacterial products induce IL-6/STAT-3 signaling and thereby inhibit the hepatic DC activation/maturation.…”

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

“…In a similar model, hepcidin was shown to exert its intrinsic antiinflammatory effect through the phosphorylation of Stat3 (33). While this could be relevant to liver transplantation given the immunoregulatory function of Stat3 (34)(35)(36)(37), the role of hepcidin and iron metabolism in models of immune-mediated liver diseases has yet to be investigated. Ours is therefore the first report to our knowledge indicating that modulation of hepcidin expression and redistribution of intra-graft iron stores could be involved in the capacity of the liver allograft to restrain alloreactive immune responses.…”

Hepatic antigen-presenting cells and regulation of liver transplant outcome

“…However, in the liver, the threshold for cell activation is elevated since inflammation does not usually occur, despite the presence of microbial products. We were the first to document molecular mechanisms that may explain the limited response of hepatic DC to specific ligands [3][4][5], resulting in reduced or altered activation of hepatic innate and adaptive immune responses and their contribution to the tolerogenic liver milieu. Nevertheless, these inherent control mechanisms can be overcome under conditions that include hepatic ischemia-reperfusion (I/R) injury and the inflammatory responses that accompany liver allograft rejection.…”