Kupffer cells potentiate liver sinusoidal endothelial cell injury in sepsis by ligating programmed cell death ligand-1

Abstract

PD-1 and PD-L1 have been reported to provide peripheral tolerance by inhibiting TCR-mediated activation. We have reported that PD-L1-/- animals are protected from sepsis-induced mortality and immune suppression. Whereas studies indicate that LSECs normally express PD-L1, which is also thought to maintain local immune liver tolerance by ligating the receptor PD-1 on T lymphocytes, the role of PD-L1 in the septic liver remains unknown. Thus, we hypothesized initially that PD-L1 expression on LSECs protects them from sepsis-induced injury. We noted that the increased vascular permeability and pSTAT3 protein expression in whole liver from septic animals were attenuated in the absence of PD-L1. Isolated LSECs taken from septic animals, which exhibited increased cell death, declining cell numbers, reduced cellular proliferation, and VEGFR2 expression (an angiogenesis marker), also showed improved cell numbers, proliferation, and percent VEGFR2(+) levels in the absence of PD-L1. We also observed that sepsis induced an increase of liver F4/80(+)PD-1(+)-expressing KCs and increased PD-L1 expression on LSECs. Interestingly, PD-L1 expression levels on LSECs decreased when PD-1(+)-expressing KCs were depleted with clodronate liposomes. Contrary to our original hypothesis, we document here that increased interactions between PD-1(+) KCs and PD-L1(+) LSECs appear to lead to the decline of normal endothelial function-essential to sustain vascular integrity and prevent ALF. Importantly, we uncover an underappreciated pathological aspect of PD-1:PD-L1 ligation during inflammation that is independent of its normal, immune-suppressive activity.

Identification of B7-H1 as a Novel Mediator of the Innate Immune/Proinflammatory Response as well as a Possible Myeloid Cell Prognostic Biomarker in Sepsis

“…Also, the impact of B7-H1 gene deficiency may include actions mediated through immune: non-immune cells (27). We have recently reported that the increased expression of B7-H1 on mouse liver sinusoidal endothelial cell contributes to the development of liver injury following the onset of experimental sepsis (28). …”

Programmed Cell Death Receptor Ligand 1 Modulates the Regulatory T Cells’ Capacity to Repress Shock/Sepsis–Induced Indirect Acute Lung Injury by Recruiting Phosphatase Src Homology Region 2 Domain-Containing Phosphatase 1

“…β-actin was blotted as a loading control. Membranes were developed by chemiluminescence using an Amersham prime ECL plus detection system (GE Healthcare Life Sciences; Pittsburgh, PA) and densitometric analyses were performed as previously reported by our laboratory [21] .…”

Designing a fibrotic microenvironment to investigate changes in human liver sinusoidal endothelial cell function

“…Although, matrix properties can affect LSEC phenotype, inflammation has also been shown to lead to a similar outcome [11,24]. In order to test the effect of an inflammatory microenvironment, hLSEC-rKC co-cultures were investigated.…”

“…It has been shown that in response to bile duct ligation in a rat model there is an increase in the number of KCs present in the liver correlating with an increase in the degree of fibrosis [23]. The study by Hutchins et al [24] reported that in response to cecal ligation and puncture surgery to induce sepsis in mouse models KCs acted as potentiators of LSEC injury. The authors reported an increase in the interaction of programmed death receptor 1 (PDR1) on KCs with programmed death ligand 1 on LSECs leading to the decline of normal endothelial function.…”