CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia-reperfusion injury in mice

Abstract

Hepatic innate immune cells, in particular interstitial dendritic cells (DC), regulate inflammatory responses and may promote inherent liver tolerogenicity. Following tissue injury, adenosine triphosphate (ATP) is released and acts as a damage-associated molecular pattern that activates innate immune cells via pattern recognition receptors. CD39 (ectonucleoside triphosphate diphosphohydrolase-1) rapidly hydrolyzes extracellular ATP to maintain physiological levels. We hypothesized that CD39 expression on liver DC might contribute to regulation of their innate immune functions. Mouse liver conventional myeloid (m) DC were hyporesponsive to ATP compared with their splenic counterparts. This disparity was ascribed to more efficient hydrolysis of ATP by higher expression of CD39 on liver mDC. Human liver mDC expressed greater levels of CD39 than those from peripheral blood. The comparatively high expression of CD39 on liver mDC correlated strongly with both ATP hydrolysis and adenosine production. Notably, CD39-/- mouse liver mDC exhibited a more mature phenotype, greater responsiveness to Toll-like receptor 4 ligation, and stronger pro-inflammatory and immunostimulatory activity than wild-type (WT) liver mDC. To investigate the role of CD39 on liver mDC in vivo, we performed orthotopic liver transplantation with extended cold preservation using CD39-/- or WT donor mouse livers. Compared with WT liver grafts, CD39-/- grafts exhibited enhanced interstitial DC activation, elevated proinflammatory cytokine levels, and more severe tissue injury. Moreover, portal venous delivery of WT but not CD39-/- liver mDC to donor livers immediately post-transplant exerted a protective effect against graft injury in CD39-/- to CD39-/- liver transplantation. These data reveal that CD39 expression on conventional liver mDC limits their pro-inflammatory activity and confers protective properties on these important innate immune cells against liver transplant ischemia/reperfusion injury.

Characterization of 11C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation

“…These data are consistent with prior reports implicating liver as a primary route of lipopolysaccharide clearance during bacterial sepsis (27,28). Moreover, hepatic myeloid interstitial dendritic cell ectonucleoside triphosphate diphosphohydrolase-1 (CD39) hyporesponsiveness has been reported in mice (29). Combined, the aforementioned processes would result in an accumulation of lipopolysaccharide, activation of hepatic Toll-like receptor 4, and suppression of extracellular adenosinetriphosphate hydrolysis (via CD39 hyporesponsiveness) and thus stimulate upregulation of P2X7R expression.…”

Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity

“…Vero, Vero-7b (7), and 293T cells were cultured in DMEM containing 5% (vol/vol) FBS and P/S. hHEPs were isolated and cultured as described (53,54). hPADs (PT-5020; Lonza) were maintained with PBM-2 Basal Medium (Lonza).…”

Stellate Cells in Hepatic Immunological Tolerance

“…Both conventional myeloid (m) DCs and nonconventional (Type-1 IFN-producing) plasmacytoid (p) DCs are present in the liver, mDCs being predominant. Despite being a minor population (<1%) of the NPCs, DCs play an important role in ischemia-reperfusion injury [79][80][81][82][83], hepatic fibrosis [84,85], and can regulate liver allograft tolerance [5,86]. Interestingly, compared to the peripheral DCs, liver DCs express low levels of MHC class II, adhesion molecules and costimulatory molecules, are resistant to maturation, and can downregulate effector T cell responses [5].…”