Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation

Kumar, Sudhir; Wang, Jiang; Thomson, Angus W.; Gandhi, Chandrashekhar R.

doi:10.1189/jlb.2a0516-239r

Cited by 27 publications

(20 citation statements)

References 53 publications

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“…To our knowledge, whether IDO1 expression by human PCs is involved in Treg induction has not been examined. Mouse liver PCs, also known as hepatic stellate cells, however, have been shown to promote the suppressive function of natural Treg through hepatic stellate cell-expressed IDO1 and activation of the aryl hydrocarbon receptor (29).…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

Liu¹,

Merola²,

Manes³

et al. 2018

JCI Insight

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Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM, but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces γ-PC-mediated immunoregulatory effects. Furthermore, human PCs express IDO1 in a skin allograft rejection humanized mouse model and in human renal allografts with acute T cell-mediated rejection. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

Liu¹,

Merola²,

Manes³

et al. 2018

JCI Insight

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“…Sections were then washed 3 times with PBS/ 0.005% Tween20, incubated with secondary Ab (1:1000) (Goat anti-Rabbit IgG-Alexa Fluor 568; Thermo Fisher Scientific) for 1 h at room temperature, and mounted with DAPI for nuclear staining. Images were acquired with an Olympus microscope (Olympus, Tokyo, Japan) (5,13,14).…”

Section: Liver Histology and Immunohistochemistrymentioning

confidence: 99%

Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA‐540 expression

et al. 2018

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Levels of augmenter of liver regeneration (ALR), a multifunctional protein, are reduced in steatohepatitis. ALR depletion from ALRflox/flox/Alb‐Cre [ALR‐L‐knockout (KO)] mouse causes robust steatosis and apoptosis of hepatocytes, and pericellular fibrosis between 1 and 2 wk postbirth. Steatosis regresses by 4 wk upon reappearance of ALR‐expressing hepatocytes. We investigated mechanisms of ALR depletion‐induced steatosis. ALR‐L‐KO mice (1‐, 2‐, and 4 wk old) and Adeno‐Cre‐transfected ALRflox/flox hepatocytes were used for in vivo and in vitro studies. ALR depletion from hepatocytes in vivo downregulated peroxisome proliferator‐activated receptor (PPAR)‐α, carnitine palmitoyl transferase I (CPTl)a, peroxisomal membrane protein 70 (PMP70) (modest down‐regulation), and acyl‐CoA oxidase 1 (ACOX1). The markedly up‐regulated (20X) novel microRNA‐540 (miR‐540) was identified to target PPARα, PMP70, ACOX1, and CPT1a. ALR depletion from primary hepatocytes increased oxidative stress, miR‐540 expression, and steatosis and down‐regulated PPARα, ACOX1, PMP70, and CPT1a expression. Anti‐miR‐540 mitigated ALR depletion‐induced steatosis and prevented loss of PPARα, ACOX1, PMP70, and CPT1a expression. Antioxidant N‐acetylcysteine and recombinant ALR (rALR) both inhibited ALR depletion‐induced miR‐540 expression and lipid accumulation in hepatocytes. Finally, treatment of ALR‐L‐KO mice with rALR between 1 and 2 wk prevented miR‐540 expression, and arrested steatosis and fibrosis. We conclude that ALR deficiency‐mediated oxidative stress induces generation of miR‐540, which promotes steatosis by dysregulating peroxisomal and mitochondrial lipid homeostasis.—Kumar, S., Rani, R., Karns, R., Gandhi, C. R. Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA‐540 expression. FASEB J. 33, 3825–3840 (2019). http://www.fasebj.org

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“…Our earlier work showed significantly lower influx of CD4 ϩ T cells in ConA-challenged HSC-depleted mice and the extent of NKT cells did not change (16). Indeed, we have shown that HSCs play a critical role in recruitment of and cross-communication with circulating and resident immune cells (6,18,28,39). Because, TNF␣ and type I and type II IFNs increase nuclear IRF1 (40,41), based on our data, it can be concluded that IRF1 is that common pathway of liver cell injury.…”

Section: Discussionmentioning

confidence: 64%

“…Because HSCs do not produce IFN␥ (18, 19, 28), it is apparent that IFN␤ released by ConA-stimulated HSCs increase expression of IRF1 and its nuclear translocation in hepatocytes. We have previously shown that HSCs have an impressive ability to not only attract immune cells (CD4 ϩ T cells, CD4 ϩ CD25 ϩ FoxP3 ϩ regulatory (Treg) cells, and dendritic cells) but also modulate their characteristics skewing toward liver's immunotolerance, and the bidirectional interactions between co-cultured HSCs and immune cells influence the net synthesis of cytokines and chemokines (6,18,28). Because HSC-depleted mice are protected from ConA-induced injury (16), it is evident that HSCs play an important role in IFN␥ production by CD4 ϩ and NKT cells.…”

Section: Distinct Effects Of Irf1 In Stellate Cells and Hepatocytesmentioning

confidence: 99%

Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury

Rani

Kumar

Sharma

et al. 2018

Journal of Biological Chemistry

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Concanavalin A (ConA)‐induced liver injury in mice has been used extensively as a model to understand the role of immune cells. However, perisinusoidal hepatic stellate cells (HSCs), the primary cell type of liver fibrosis, were recently found to orchestrate ConA‐induced liver damage directly and by influencing recruitment and characteristics of immune cells. HSC‐released interferon‐β (IFNβ) and increased hepatic expression of a transcription factor, interferon regulatory factor 1 (IRF1), were determined to be major components of ConA‐induced liver injury. The aim of this study was to delineate the mechanisms of the actions of ConA on HSCs with specific focus on IRF1/IFNβ axis. HSCs and hepatocytes isolated from WT and IRF1−/− mice were used. HSCs were found to rapidly internalize FITC‐labeled ConA; internalized ConA was greatly concentrated in the perinuclear region. ConA increased the expression and nuclear translocation of IRF1 and NF‐κB in wild type (WT) HSCs and the expression of TNFα, IFNβ and CXCL1. These effects of ConA were abrogated in HSCs isolated from IRF1−/− mice. ConA induced JAK/STAT signaling in HSCs, and inhibitors of this signaling pathway ameliorated ConA‐induced IRF1 expression/nuclear translocation as well as cytokine/chemokine production. Finally, ConA‐stimulated WT but not IRF1−/− HSCs induced apoptosis of WT hepatocytes. Conversely, ConA‐stimulated WT HSCs were unable to induce apoptosis of IRF1−/− hepatocytes. Our findings suggest that IRF1 plays a dual role in ConA‐induced liver injury. On the one hand, ConA stimulates the synthesis of the mediators of hepatocyte injury through JAK/STAT signaling involving IRF1. On the other hand, IRF1 nuclear translocation in hepatocytes induced by ConA‐stimulated HSCs instigates apoptosis. While this mechanistic evaluation is performed using ConA, the findings could be relevant to liver injury due to lectins in the food products. In conclusion, HSC can be a potential therapeutic target for acute liver damage of various etiologies including lectins. Support or Funding Information This work was supported by a VA Merit Review Award 1IO1BX001174 to CRG. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation

Cited by 27 publications

References 53 publications

Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA‐540 expression

Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury

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