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Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis.

ABSTRACT: The role of the different lymphocyte populations in liver microenvironment of chronic hepatitis C (CHC) patients is still matter of debate. Since Th17 and Treg have opposite functions, their balance could affect disease progression. The aim was to explore liver microenvironment and its peripheral blood counterpart in adult CHC patients. CD4⁺ lymphocytes were predominant in the liver, with high Foxp3⁺ but low IL-17A⁺ frequency. IL-17A⁺ lymphocytes and IL-17A⁺/Foxp3⁺ ratio displayed association with advanced fibrosis (p?=?0.0130; p?=?0.0236, respectively), while Foxp3⁺ lymphocytes and IL-10 expression level inversely correlated with fibrosis severity (p?=?0.0381, p?=?0.0398, respectively). TGF-?/IL-6 ratio correlated with IL-17A⁺/Foxp3⁺ ratio (p?=?0.0036, r?=?0.5944) and with IL-17A⁺ lymphocytes (p?=?0.0093; r?=?0.5203). TNF-? and TGF-? were associated with hepatitis severity (p?=?0.0409, p?=?0.0321). Peripheral blood lymphocyte frequency was not associated with liver damage. There are functionally different immune cell populations actively involved in liver damage, but the liver cytokine milieu actually drives the pathogenesis. The intrahepatic Foxp3⁺ lymphocytes predominance beside the low IL-17A⁺ lymphocytes frequency, delineate a skewed IL-17A⁺/Foxp3⁺ balance towards Foxp3⁺ lymphocytes. However, the IL-17A⁺ lymphocytes association with advanced fibrosis denotes their role in the pathogenesis. Therefore, the interplay between Th17 and Treg conditions liver fibrogenesis.

SUBMITTER: Rios DA

PROVIDER: S-EPMC5643436 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis.

Rios Daniela Alejandra DA Valva Pamela P Casciato Paola Cecilia PC Frias Silvia S Soledad Caldirola María M Gaillard María Isabel MI Bezrodnik Liliana L Bandi Juan J Galdame Omar O Ameigeiras Beatriz B Krasniansky Diana D Brodersen Carlos C Mullen Eduardo E Matteo Elena Noemí De EN Preciado María Victoria MV

Scientific reports 20171016 1

The role of the different lymphocyte populations in liver microenvironment of chronic hepatitis C (CHC) patients is still matter of debate. Since Th17 and Treg have opposite functions, their balance could affect disease progression. The aim was to explore liver microenvironment and its peripheral blood counterpart in adult CHC patients. CD4+ lymphocytes were predominant in the liver, with high Foxp3+ but low IL-17A+ frequency. IL-17A+ lymphocytes and I ...[more]

PMID: 29038590

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Project description:BackgroundHepatitis B virus-related liver fibrosis (HBV-LF) always progresses from inflammation to fibrosis. However, the relationship between these two pathological conditions is not fully understood. Here, it is postulated that the balance between regulatory T (Treg) cells and T helper 17 (Th17) cells as an indicator of inflammation may predict fibrosis progression of HBV-LF.Methodology/principal findingsThe frequencies and phenotypes of peripheral Treg and Th17 cells of seventy-seven HBeAg-positive chronic hepatitis B (CHB) patients who underwent liver biopsies and thirty healthy controls were determined by flow cytometry. In the periphery of CHB patients, both Treg and Th17 frequencies were significantly increased and correlated, and a lower Treg/Th17 ratio always indicated more liver injury and fibrosis progression. To investigate exact effects of Treg and Th17 cells during HBV-LF, a series of in vitro experiments were performed using purified CD4(+), CD4(+)CD25(+), or CD4(+)CD25(-) cells from the periphery, primary human hepatic stellate cells (HSCs) isolated from healthy liver specimens, human recombinant interleukin (IL)-17 cytokine, anti-IL-17 antibody and HBcAg. In response to HBcAg, CD4(+)CD25(+) cells significantly inhibited cell proliferation and cytokine production (especially IL-17 and IL-22) by CD4(+)CD25(-) cells in cell-contact and dose-dependent manners. In addition, CD4(+) cells from CHB patients, compared to those from HC subjects, dramatically promoted proliferation and activation of human HSCs. Moreover, in a dramatically dose-dependent manner, CD4(+)CD25(+) cells from CHB patients inhibited, whereas recombinant IL-17 response promoted the proliferation and activation of HSCs. Finally, in vivo evidence about effects of Treg/Th17 balance during liver fibrosis was obtained in concanavalin A-induced mouse fibrosis models via depletion of CD25(+) or IL-17(+) cells, and it's observed that CD25 depletion promoted, whereas IL-17 depletion, alleviated liver injury and fibrosis progression.Conclusions/significanceThe Treg/Th17 balance might influence fibrosis progression in HBV-LF via increase of liver injury and promotion of HSCs activation.

Project description:UnlabelledHepatitis C virus (HCV) infection is associated with hepatic and extrahepatic manifestations, including immunological disorders. Chronic Hepatitis C (CHC) is often characterized by cholesterol and lipid metabolism alterations, leading to hepatic steatosis. Cholesterol metabolism, in fact, is crucial for the viral life cycle. Recent works described that a higher dietary cholesterol intake is associated with the progression of HCV-related liver disease. CHC patients have increased levels of T helper 17 (Th17)-cells, a lymphocytic population involved in the pathogenesis of liver inflammation and autoimmune hepatitis. The balance between Th17 and regulatory T (Treg) cells is crucial for chronic inflammation and autoimmunity. Th17-cell differentiation is deeply influenced by the activation LXRs, nuclear receptors modulating cholesterol homeostasis. Moreover, HCV may affect these nuclear receptors, and cholesterol metabolism, through both direct and indirect mechanisms. On these bases, we hypothesized that modulation of cholesterol levels through Normocaloric Low Cholesterol Diet (NLCD) may represent an innovative strategy to reduce the progression of HCV infection, through the modulation of peripheral Th17/Treg balance. To this end, we performed a pilot study to investigate whether a Normocaloric Low Cholesterol Diet may be able to modulate Th17/Treg balance in patients affected by chronic HCV infection. After 30 days of NLCD CHC patients showed a significant reduction in Th17 cells frequency, which correlated with strong reduction of IL-17 and IL-22 serum levels. At the same time, we appreciated an increase in the percentage of Treg cells, thus improving Treg/Th17 balance. Moreover, we observed an increased expression of LXRs and their target genes: SREBP-1c and ABCA-1. In conclusion, NLCD finely regulates Th17/Treg balance, improving immune system response in CHC patients. This study could pave the way for new treatments of CHC patients, suggesting that change in lifestyle could support the management of these patients, promoting well-being and possibly hindering disease progression.Trial registrationClinicalTrials.gov NCT02038387.

Dataset Information

Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis.

Publications

Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis.

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