Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver

Neumann, Katrin; Erben, Ulrike; Kruse, Nils; Wechsung, Katja; Schümann, Michael; Klugewitz, Katja; Scheffold, Alexander; Kühl, Anja A.

doi:10.1371/journal.pone.0123867

Cited by 28 publications

(17 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although HBV is the prototype of the hepadnavirus family, whose primary host is the hepatocyte, HSECs are also capable of HBV particle uptake (47), which means that it is possible that HBV DNA sensing occurs in these cells. In addition to producing chemokines themselves, HSECs also possess chemokine transfer functions (48). As the major route by which circulating immune cells enter the liver (43, 49), HSEC-mediated increases in chemokine levels are an indication of liver inflammation and mediate the efficient recruitment of lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasm-Translocated Ku70/80 Complex Sensing of HBV DNA Induces Hepatitis-Associated Chemokine Secretion

Zheng

et al. 2016

Front. Immunol.

View full text Add to dashboard Cite

Chronic hepatitis B virus (HBV) infection remains a serious disease, mainly due to its severe pathological consequences, which are difficult to cure using current therapies. When the immune system responds to hepatocytes experiencing rapid HBV replication, effector cells (such as HBV-specific CD8+ T cells, NK cells, NKT cells, and other subtypes of immune cells) infiltrate the liver and cause hepatitis. However, the precise recruitment of these cells remains unclear. In the present study, we found that the cytoplasm-translocated Ku70/80 complex in liver-derived cells sensed cytosolic HBV DNA and promoted hepatitis-associated chemokine secretion. Upon sensing HBV DNA, DNA-dependent protein kinase catalytic subunit and PARP1 were assembled. Then, IRF1 was activated and translocated into the nucleus, which upregulated CCL3 and CCL5 expression. Because CCR5, a major chemokine receptor for CCL3 and CCL5, is known to be critical in hepatitis B, Ku70/80 sensing of HBV DNA likely plays a critical role in immune cell recruitment in response to HBV infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytoplasm-Translocated Ku70/80 Complex Sensing of HBV DNA Induces Hepatitis-Associated Chemokine Secretion

Zheng

et al. 2016

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…CXCL9-11 are important for T cell recruitment and transmigration following endothelial activation with IFNγ and TNFα ( Curbishley et al, 2005 ). These chemokine ligands are produced by neighbouring cells and can be transcytosed by LSEC and presented on their cell surface ( Middleton et al, 2002 ; Schrage et al, 2008 ; Neumann et al, 2015 ). They can also be circulated within the sinusoids and captured by proteoglycans within the endothelial cell glycocalyx ( Curbishley et al, 2005 ).…”

Section: Immunological Role Of Lsecmentioning

confidence: 99%

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

View full text Add to dashboard Cite

Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.

show abstract

“…The hepatic proinflammatory state in virulent MHV3-infected mice leads to rapid but transient intrahepatic recruitment of inflammatory cells and decreases of B, CD4, and CD8 lymphocyte subsets. LSECs are responsible for the recruitment and transmigration of leukocytes during liver inflammation (35). We postulated that higher production of chemokines in the livers of MHV3-infected mice induced higher recruitment of inflammatory cells than in mice infected with attenuated virus strains.…”

Section: Lower Tropism Of Attenuated Mhv3 Variants For Lsecs Is Assocmentioning

confidence: 99%

Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis

Bleau

Filliol

Samson

et al. 2016

J Virol

View full text Add to dashboard Cite

Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. IMPORTANCEViral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million people worldwide, respectively. It has been suggested that a balance between protection and liver damage mediated by the host's immune response during the acute phase of infection would be determinant in hepatitis outcome. Thus, it appears crucial to identify the factors that predispose in exacerbating liver inflammation to limit hepatocyte injury. Liver sinusoidal endothelial cells (LSECs) can express both anti-and proinflammatory functions, but their role in acute viral hepatitis has never been investigated. Using mouse hepatitis virus (MHV) infections as animal models of viral hepatitis, we report for the first time that in vitro and in vivo infection of LSECs by the pathogenic MHV3 serotype leads to a reversion of their intrinsic anti-inflammatory phenotype toward a proinflammatory profile as well to as disorders in vascular factors, correlating with the severity of hepatitis. These results highlight a new virus-promoted mechanism of exacerbation of liver inflammatory response during acute hepatitis. U nder physiological conditions, the liver adopts mech...

show abstract

Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver

Cited by 28 publications

References 63 publications

Cytoplasm-Translocated Ku70/80 Complex Sensing of HBV DNA Induces Hepatitis-Associated Chemokine Secretion

Cytoplasm-Translocated Ku70/80 Complex Sensing of HBV DNA Induces Hepatitis-Associated Chemokine Secretion

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis

Contact Info

Product

Resources

About