IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells

Dudek, Michael; Lohr, Kerstin; Donakonda, Sainitin; Baumann, Tobias; Lüdemann, Max; Hegenbarth, Silke; Dübbel, Lena; Eberhagen, Carola; Michailidou, Savvoula; Yassin, Abdallah; Prinz, Marco; Popper, Bastian; Rose–John, Stefan; Zischka, Hans; Knolle, Percy

doi:10.1016/j.celrep.2022.110389

Cited by 16 publications

(18 citation statements)

References 58 publications

(76 reference statements)

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“…[69] Additional details of the tolerogenic mechanisms of LSECs have recently been described, revealing that LSECs block metabolic changes that are associated with a more immunogenic Ag-presenting phenotype in response to lipopolysaccharide in other Ag-presenting cells, and that LSEC-primed CD8 T cells develop into a unique population of memory cells through IL-6 transsignaling and Stat3 signaling leading to upregulation of FOXO1. [70] In chronic liver disease, however, these tolerogenic properties of LSECs may be altered, as shown in an animal model of cirrhosis in which LSECs functioned as Ag-presenting cells to stimulate a proinflammatory CD4 + Th17 T-cell response. [71] Because of their propensity for inducing tolerance, LSECs are an intriguing target for therapeutics for autoimmune disease.…”

Section: Lsec Modulation Of Adaptive Immunitymentioning

confidence: 99%

The evolving role of liver sinusoidal endothelial cells in liver health and disease

et al. 2023

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LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.

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Section: Lsec Modulation Of Adaptive Immunitymentioning

confidence: 99%

The evolving role of liver sinusoidal endothelial cells in liver health and disease

et al. 2023

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“…LSECs are also highly effective inducers of CD8 T cell tolerance [ 52 , 57 ], owed to their remarkable capacity to cross-present antigens taken up by endocytosis [ 57 , 58 ]. LSECs are also able to induce CD8 memory T cells, which remain non-responsive during steady-state and require strong signals for re-activation [ 59 , 60 ]. Accordingly, nanoparticle-mediated delivery of MHC I–restricted autoantigen peptide was found to induce antigen-specific CD8 T cell tolerance and protection from antigen-driven cholangitis [ 61 ].…”

Section: Liver Tolerancementioning

confidence: 99%

Harnessing the liver to induce antigen-specific immune tolerance

2022

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Autoimmune diseases develop when the adaptive immune system attacks the body’s own antigens leading to tissue damage. At least 80 different conditions are believed to have an autoimmune aetiology, including rheumatoid arthritis, type I diabetes, multiple sclerosis or systemic lupus erythematosus. Collectively, autoimmune diseases are a leading cause of severe health impairment along with substantial socioeconomic costs. Current treatments are mostly symptomatic and non-specific, and it is typically not possible to cure these diseases. Thus, the development of more causative treatments that suppress only the pathogenic immune responses, but spare general immunity is of great biomedical interest. The liver offers considerable potential for development of such antigen-specific immunotherapies, as it has a distinct physiological capacity to induce immune tolerance. Indeed, the liver has been shown to specifically suppress autoimmune responses to organ allografts co-transplanted with the liver or to autoantigens that were transferred to the liver. Liver tolerance is established by a unique microenvironment that facilitates interactions between liver-resident antigen-presenting cells and lymphocytes passing by in the low blood flow within the hepatic sinusoids. Here, we summarise current concepts and mechanisms of liver immune tolerance, and review present approaches to harness liver tolerance for antigen-specific immunotherapy.

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“…In addition, CD8+T cells activated by liver sinusoidal endothelial cells (LSEC) display a transient burst of oxidative phosphorylation and glycolysis. Co-stimulation of IL-6 signals ensures a high expression of FOXO1 in LSEC-derived CD8+T cells, which subsequently reduces metabolic activities related to T cell activation [54] , [58] . Conversely, glucose transporter 4 (GLUT4) inhibitor WZB117 is capable of effectively blocking the stimulating effect of glucose on LPS-induced mRNA expression of IL-6, indicating that a high level of blood glucose could stimulate the expression of IL-6 [59] .…”

Section: Role Of Il-6 In Metabolismmentioning

confidence: 99%

Roles of Interleukin-6-mediated immunometabolic reprogramming in COVID-19 and other viral infection-associated diseases

Ren

Cao

2022

International Immunopharmacology

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IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells

Cited by 16 publications

References 58 publications

The evolving role of liver sinusoidal endothelial cells in liver health and disease

The evolving role of liver sinusoidal endothelial cells in liver health and disease

Harnessing the liver to induce antigen-specific immune tolerance

Roles of Interleukin-6-mediated immunometabolic reprogramming in COVID-19 and other viral infection-associated diseases

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