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Topchieva LV, Kurbatova IV, Dudanova OP, Vasileva AV, Zhulai GA. Immune cell balance as potential biomarker of progressing non-alcoholic fatty liver disease. GENES & CELLS 2024; 19:105-125. [DOI: 10.17816/gc610252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic, slowly progressive metabolic multifactorial disease. It is represented by several clinical and morphological forms: steatosis, nonalcoholic steatohepatitis (NASH) (with or without fibrosis), and liver cirrhosis. The search for minimally invasive and cost-effective biomarkers of NAFLD is a key task in the diagnosis, staging of progression, and long-term monitoring of NAFLD. This article discusses the possibility of using immune cell balance as potential minimally invasive peripheral markers of NAFLD progression. In the progression of NASH from steatosis to fibrosis and cirrhosis, inflammation plays an important role because of the activation of Kupffer cells and increased migration of monocytes, dendritic cells, neutrophils, and activated T lymphocytes into the tissues. Macrophages originating from monocytes, with NASH progression, gradually begin to prevail over the pool of resident macrophages. The risk of NASH and fibrosis development in patients with NAFLD increases with the ratio of neutrophils/lymphocytes in the liver. An increase in the Th17 cell count and a decrease in T-regulatory cell count can contribute to increased hepatic steatosis and inflammation development in NAFLD and accelerate the transition from simple steatosis to steatohepatitis and fibrosis. Information on the participation of noncoding RNAs in the regulation of the balance of immune cells in NAFLD is presented, which also allows us to consider them as additional, along with cellular, markers of disease progression.
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2
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Cuño-Gómiz C, de Gregorio E, Tutusaus A, Rider P, Andrés-Sánchez N, Colell A, Morales A, Marí M. Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice. Biol Sex Differ 2023; 14:85. [PMID: 37964320 PMCID: PMC10644614 DOI: 10.1186/s13293-023-00569-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/06/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in Western countries, evolving into metabolic dysfunction-associated steatohepatitis (MASH) with a sexual dimorphism. Fertile women exhibit lower MASLD risk than men, which diminishes post-menopause. While NKT-cell involvement in steatohepatitis is debated, discrepancies may stem from varied mouse strains used, predominantly C57BL6/J with Th1-dominant responses. Exploration of steatohepatitis, encompassing both genders, using Balb/c background, with Th2-dominant immune response, and CD1d-deficient mice in the Balb/c background (lacking Type I and Type II NKT cells) can clarify gender disparities and NKT-cell influence on MASH progression. METHODS A high fat and choline-deficient (HFCD) diet was used in male and female mice, Balb/c mice or CD1d-/- mice in the Balb/c background that exhibit a Th2-dominant immune response. Liver fibrosis and inflammatory gene expression were measured by qPCR, and histology assessment. NKT cells, T cells, macrophages and neutrophils were assessed by flow cytometry. RESULTS Female mice displayed milder steatohepatitis after 6 weeks of HFCD, showing reduced liver damage, inflammation, and fibrosis compared to males. Male Balb/c mice exhibited NKT-cell protection against steatohepatitis whereas CD1d-/- males on HFCD presented decreased hepatoprotection, increased liver fibrosis, inflammation, neutrophilic infiltration, and inflammatory macrophages. In contrast, the NKT-cell role was negligible in early steatohepatitis development in both female mice, as fibrosis and inflammation were similar despite augmented liver damage in CD1d-/- females. Relevant, hepatic type I NKT levels in female Balb/c mice were significantly lower than in male. CONCLUSIONS NKT cells exert a protective role against experimental steatohepatitis as HFCD-treated CD1d-/- males had more severe fibrosis and inflammation than male Balb/c mice. In females, the HFCD-induced hepatocellular damage and the immune response are less affected by NKT cells on early steatohepatitis progression, underscoring sex-specific NKT-cell influence in MASH development.
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Affiliation(s)
- Carlos Cuño-Gómiz
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain
| | - Estefanía de Gregorio
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain
| | - Nuria Andrés-Sánchez
- Institute of Molecular Genetics of Montpellier (IGMM), University of Montpellier, CNRS, INSERM, 34293, Montpellier, France
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain.
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain.
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Yang Zhou J. Innate immunity and early liver inflammation. Front Immunol 2023; 14:1175147. [PMID: 37205101 PMCID: PMC10187146 DOI: 10.3389/fimmu.2023.1175147] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/30/2023] [Indexed: 05/21/2023] Open
Abstract
The innate system constitutes a first-line defence mechanism against pathogens. 80% of the blood supply entering the human liver arrives from the splanchnic circulation through the portal vein, so it is constantly exposed to immunologically active substances and pathogens from the gastrointestinal tract. Rapid neutralization of pathogens and toxins is an essential function of the liver, but so too is avoidance of harmful and unnecessary immune reactions. This delicate balance of reactivity and tolerance is orchestrated by a diverse repertoire of hepatic immune cells. In particular, the human liver is enriched in many innate immune cell subsets, including Kupffer cells (KCs), innate lymphoid cells (ILCs) like Natural Killer (NK) cells and ILC-like unconventional T cells - namely Natural Killer T cells (NKT), γδ T cells and Mucosal-associated Invariant T cells (MAIT). These cells reside in the liver in a memory-effector state, so they respond quickly to trigger appropriate responses. The contribution of aberrant innate immunity to inflammatory liver diseases is now being better understood. In particular, we are beginning to understand how specific innate immune subsets trigger chronic liver inflammation, which ultimately results in hepatic fibrosis. In this review, we consider the roles of specific innate immune cell subsets in early inflammation in human liver disease.
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Affiliation(s)
- Jordi Yang Zhou
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
- *Correspondence: Jordi Yang Zhou,
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Zheng S, Yang W, Yao D, Tang S, Hou J, Chang X. A comparative study on roles of natural killer T cells in two diet-induced non-alcoholic steatohepatitis-related fibrosis in mice. Ann Med 2022; 54:2233-2245. [PMID: 35950602 PMCID: PMC9377241 DOI: 10.1080/07853890.2022.2108894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Immune responses are important in the progression of non-alcoholic fatty liver disease (NAFLD). Natural killer T (NKT) cells are main components of the innate immune system that modulate immunity. However, the role of NKT cells in NAFLD remains controversial. OBJECTIVE We aimed to investigate the role of NKT cells in non-alcoholic steatohepatitis (NASH)-related fibrosis in fast food diet (FFD)- and methionine choline-deficient (MCD) diet-induced mouse models. METHODS Hepatic NKT cells were analysed in wild-type (WT) and CD1d-/- mice fed FFD or MCD diets. Hepatic pathology, cytokine profiles and liver fibrosis were evaluated. Furthermore, the effect of chronic administration of α-galactosylceramide (α-GalCer) on liver fibrosis was investigated in both FFD- and MCD-treated mice. RESULTS FFD induced a significant depletion of hepatic NKT cells, thus leading to mild to moderate NASH and early-stage fibrosis, while mice fed MCD diets developed severe liver inflammation and progressive fibrosis without a significant change in hepatic NKT cell abundance. FFD induced a similar liver fibrogenic response in CD1d-/- and WT mice, while MCD induced a higher hepatic mRNA expression of Col1α1 and TIMP1 as well as relative fibrosis density in CD1d-/- mice than WT mice (31.8 vs. 16.3, p = .039; 40.0 vs. 22.6, p = .019; 2.24 vs. 1.59, p = .036). Chronic administration of α-GalCer induced a higher hepatic mRNA expression of TIMP1 in MCD-treated mice than controls (36.7 vs. 14.9, p = .005). CONCLUSION NKT cells have protective roles in NAFLD as the disease progresses. During diet-induced steatosis, mild to moderate NASH and the early stage of fibrosis, hepatic NKT cells are relatively depleted, leading to a proinflammatory status. In severe NASH and the advanced stage of liver fibrosis, NKT cells play a role in inhibiting the NASH-related fibrogenic response. Chronic administration of α-GalCer induces NKT cell anergy and tolerance, which may play a role in promoting the liver fibrogenic response.
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Affiliation(s)
- Shumei Zheng
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Wenzhuo Yang
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Shanghai Tongji University, Shanghai, China
| | - Dongmei Yao
- Department of Gastroenterology and Hepatology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shanhong Tang
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Juanni Hou
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xing Chang
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
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Kandhi R, Variya B, Ramanathan S, Ilangumaran S. An improved method for isolation and flow cytometric characterization of intrahepatic leukocytes from fatty and fibrotic liver tissues. Anat Rec (Hoboken) 2022; 306:1011-1030. [PMID: 35848859 DOI: 10.1002/ar.25039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/28/2022] [Accepted: 06/28/2022] [Indexed: 12/11/2022]
Abstract
Flow cytometry is an imperative tool to characterize alterations in a wide range of immune cell populations during inflammatory conditions and disease states that affect the liver such as the obesity-induced non-alcoholic fatty liver disease and liver fibrosis. Identification and quantification of immune cell subsets from the liver is critically dependent on efficient isolation of intrahepatic leukocytes. The isolation of leukocytes from fatty and fibrotic livers and processing the cells for flow cytometry can be challenging with respect to cell yields, purity and most importantly, the level of autofluorescence resulting from fat deposition. Here, we describe an efficient method for isolating intrahepatic leukocytes from mice fed with high fat diet and propose a strategy to alleviate autofluorescence during phenotyping by multicolor flowcytometry. We also describe a gating strategy for robust identification of granulocytes, pro-inflammatory, anti-inflammatory and transitional state monocyte subsets, dendritic cells, B cell, T lymphocyte subpopulations and NK cell subsets. Overall, the procedures described here will allow simultaneous processing of several samples while ensuring reproducible cell isolation and efficient noise reduction required for reliable characterization of intrahepatic leukocytes from the fatty liver tissues.
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Affiliation(s)
- Rajani Kandhi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Bhavesh Variya
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
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Adar T, Ya'acov AB, Shabat Y, Mizrahi M, Zolotarov L, Lichtenstein Y, Ilan Y. Steroid-mediated liver steatosis is CD1d-dependent, while steroid-induced liver necrosis, inflammation, and metabolic changes are CD1d-independent. BMC Gastroenterol 2022; 22:169. [PMID: 35392825 PMCID: PMC8991564 DOI: 10.1186/s12876-022-02242-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 03/24/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction Glucocorticoids contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Natural killer T cells play a role in the pathogenesis of NAFLD and response to steroids. The present study aimed to determine the role of CD1d in steroid-mediated metabolic derangement and the steroid-protective effect of glycosphingolipids. Methods Ten groups of mice were studied. Steroids were orally administered to C57BL/6 mice to assess the therapeutic effect of β-glucosylceramide (GC) on the development of steroid-mediated liver damage and metabolic derangements. The role of CD1d in the pathogenesis of steroid-induced liver damage and in mediating the hepatoprotective effect of GC was studied in CD1d−/− mice. Results A model of oral administration of steroids was established, resulting in insulin resistance, hyperinsulinemia, hypertriglyceridemia, liver steatosis, and hepatocellular injury. Steroid administration to CD1d−/− mice was associated with hyperglycemia and hypertriglyceridemia. However, CD1d−/− mice did not manifest marked steroid-induced steatosis. GC treatment alleviated steroid-associated metabolic derangements and liver injury independent of CD1d expression. Conclusion A steroid-mediated model of NAFLD and metabolic derangements was established in which steroid-mediated steatosis was CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes were CD1d-independent, which may support a dichotomy between steatosis and steatohepatitis in NAFLD. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02242-9.
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Affiliation(s)
- Tomer Adar
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel.,Digestive Disease Institute, Shaare-Zedek Medical Center, Jerusalem, Israel
| | - Ami Ben Ya'acov
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel.,Digestive Disease Institute, Shaare-Zedek Medical Center, Jerusalem, Israel
| | - Yehudit Shabat
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel
| | - Meir Mizrahi
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel
| | - Lida Zolotarov
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel
| | - Yoav Lichtenstein
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel
| | - Yaron Ilan
- Faculty of Medicine, Department of Medicine, Hadassah Medical Center, Hebrew University, POB 1200, 91120, Jerusalem, Israel.
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Cho Y, Rhee H, Kim YE, Lee M, Lee BW, Kang ES, Cha BS, Choi JY, Lee YH. Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study). BMC Med 2022; 20:93. [PMID: 35307033 PMCID: PMC8935785 DOI: 10.1186/s12916-022-02288-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/08/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change. RESULTS Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104). CONCLUSIONS Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population. TRIAL REGISTRATION The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 ).
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Affiliation(s)
- Yongin Cho
- Department of Endocrinology and Metabolism, Inha University School of Medicine, Incheon, Republic of Korea.,Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young-Eun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin-Young Choi
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea. .,Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul, Republic of Korea.
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Hirsova P, Bamidele AO, Wang H, Povero D, Revelo XS. Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. Front Endocrinol (Lausanne) 2021; 12:760860. [PMID: 34777255 PMCID: PMC8581300 DOI: 10.3389/fendo.2021.760860] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/14/2021] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.
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Affiliation(s)
- Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Adebowale O. Bamidele
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Haiguang Wang
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States
| | - Davide Povero
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | - Xavier S. Revelo
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States
- Center for Immunology, University of Minnesota, Minneapolis, MN, United States
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Kessoku T, Kobayashi T, Tanaka K, Yamamoto A, Takahashi K, Iwaki M, Ozaki A, Kasai Y, Nogami A, Honda Y, Ogawa Y, Kato S, Imajo K, Higurashi T, Hosono K, Yoneda M, Usuda H, Wada K, Saito S, Nakajima A. The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target. Int J Mol Sci 2021; 22:ijms22158161. [PMID: 34360923 PMCID: PMC8347478 DOI: 10.3390/ijms22158161] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.
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Affiliation(s)
- Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Correspondence: ; Tel.: +81-45-787-2640; Fax: +81-45-784-3546
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kosuke Tanaka
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Atsushi Yamamoto
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kota Takahashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yuki Kasai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Haruki Usuda
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
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10
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Wang H, Li L, Li Y, Li Y, Sha Y, Wen S, You Q, Liu L, Shi M, Zhou H. Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis. Theranostics 2021; 11:2149-2169. [PMID: 33500717 PMCID: PMC7797696 DOI: 10.7150/thno.51369] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
Rationale: Invariant natural killer T (iNKT) cells and Kupffer cells represent major hepatic populations of innate immune cells. However, their roles in steatohepatitis remain poorly understood. To elucidate their functions in steatohepatitis development, real-time, in vivo analysis is necessary to understand the pathophysiological events in the dynamic interactions between them during diet-induced steatohepatitis. Methods: We used a steatohepatitis animal model induced by a methionine-choline-deficient (MCD) diet. Multi-photon confocal live imaging and conventional experimental techniques were employed to investigate the hepatic pathological microenvironment of iNKT and Kupffer cells, interactions between them, and the biological effects of these interactions in steatohepatitis. Results: We found that iNKT cells were recruited and aggregated into small clusters and interacted dynamically with Kupffer cells in the early stage of steatohepatitis. Most significantly, the iNKT cells in the cluster cleared free lipids released by necrotic hepatocytes and presented a non-classical activation state with high IFN-γ expression. Furthermore, the Kupffer cells in the cell cluster were polarized to type M1. The transcriptome sequencing of iNKT cells showed upregulation of genes related to phagocytosis and lipid processing. Adoptive transfer of iNKT cells to Jα18-/- mice showed that iNKT and Kupffer cell clusters were essential for balancing the liver and peripheral lipid levels and inhibiting liver fibrosis development. Conclusions: Our study identified an essential role for dynamic interactions between iNKT cells and Kupffer cells in promoting lipid phagocytosis and clearance by iNKT cells during early liver steatohepatitis. Therefore, modulating iNKT cells is a potential therapeutic strategy for early steatohepatitis.
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11
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Chen C, Chang Z, Tsai F, Chen S. Cannabinoid receptor type 1 antagonist inhibits progression of obesity-associated nonalcoholic steatohepatitis in a mouse model by remodulating immune system disturbances. Immun Inflamm Dis 2020; 8:544-558. [PMID: 32798334 PMCID: PMC7654409 DOI: 10.1002/iid3.338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/23/2020] [Accepted: 07/31/2020] [Indexed: 01/15/2023] Open
Abstract
SCOPE This study investigated whether AM251, a cannabinoid receptor type 1 (CB1) antagonist, ameliorates hepatic levels of metabolic abnormalities and inflammatory responses in a murine nonalcoholic steatohepatitis (NASH) model via reversal of disturbances in the immune system. METHODS AND RESULTS Fifteen-week-old male obese db/db mice were randomly assigned to the following two groups: no treatment and treatment with AM251 at 5 mg/kg for 15 days. C57BL/6J-Lean mice were utilized as the control group. Plasma parameters, liver histopathology, and hepatic status were measured. For the in vitro study, macrophage-derived RAW264.7 cells were cultured with AM251 or CB1 small interfering RNA (siRNA) before challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of fatty acids (HFFAs). The db/db mice exhibited an increase in CB1 levels, lipid droplet accumulation, mitogen-activated protein kinase-related inflammatory responses, and macrophage and neutrophil infiltration in the liver tissues. Flow cytometry analysis revealed an elevation in macrophages and T helper cells, plus a decrease in natural killer T cells and regulatory T cells in the liver tissues of the db/db mice; treatment with 5 mg/kg AM251 reversed these changes. Moreover, in vitro experiments revealed that administration of 3.3 μM AM251 or CB1 siRNA prevented 1 mM HFFA- and 1 μΜ ACEA-induced inflammatory cytokine protein expression in the RAW264.7 cells. CONCLUSION These findings suggested that a blockade caused by CB1 reduced obesity-associated NASH progression via correction of immune system dysregulations and elevated inflammatory responses in the liver tissues.
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Affiliation(s)
- Chin‐Chang Chen
- Department of Traditional Chinese MedicineChang Gung Memorial HospitalKeelungTaiwan, ROC
- Department of Anatomy, School of MedicineChina Medical UniversityTaichungTaiwan, ROC
| | - Zi‐Yu Chang
- Department of Traditional Chinese MedicineChang Gung Memorial HospitalKeelungTaiwan, ROC
- Institute of Traditional Medicine, School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan, ROC
| | - Fuu‐Jen Tsai
- School of Chinese MedicineChina Medical UniversityTaichungTaiwan, ROC
- Department of Medical Research, Genetics CenterChina Medical University HospitalTaichungTaiwan, ROC
- Department of Medical GeneticsChina Medical University HospitalTaichungTaiwan, ROC
| | - Shih‐Yin Chen
- School of Chinese MedicineChina Medical UniversityTaichungTaiwan, ROC
- Department of Medical Research, Genetics CenterChina Medical University HospitalTaichungTaiwan, ROC
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12
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Feng D. The alteration of immune cells in the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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13
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Riffelmacher T, Kronenberg M. Metabolic Triggers of Invariant Natural Killer T-Cell Activation during Sterile Autoinflammatory Disease. Crit Rev Immunol 2020; 40:367-378. [PMID: 33463949 PMCID: PMC7116673 DOI: 10.1615/critrevimmunol.2020035158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ample evidence exists for activation of invariant natural killer T (iNKT) cells in a sterile manner by endogenous ligands or microbial antigens from the commensal flora, indicating that iNKT cells are not truly self-tolerant. Their controlled autoreactivity state is disturbed in many types of sterile inflammatory disease, resulting in their central role in modulating autoimmune responses. This review focuses on sterile iNKT-cell responses that are initiated by metabolic triggers, such as obesity-associated inflammation and fatty liver disease, as a manifestation of metabolic disease and dyslipidemia, as well as ischemia reperfusion injuries and sickle cell disease, characterized by acute lack of oxygen and oxidative stress response on reperfusion. In the intestine, inflammation and iNKT-cell response type are shaped by the microbiome as an extended "self". Disease- and organ-specific differences in iNKT-cell response type are summarized and help to define common pathways that shape iNKT-cell responses in the absence of exogenous antigen.
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Affiliation(s)
- Thomas Riffelmacher
- La Jolla Institute for Immunology, La Jolla, CA 92037
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Mitchell Kronenberg
- La Jolla Institute for Immunology, La Jolla, CA 92037
- Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093
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14
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Van Herck MA, Weyler J, Kwanten WJ, Dirinck EL, De Winter BY, Francque SM, Vonghia L. The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity. Front Immunol 2019; 10:82. [PMID: 30787925 PMCID: PMC6372559 DOI: 10.3389/fimmu.2019.00082] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 01/11/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.
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Affiliation(s)
- Mikhaïl A Van Herck
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Jonas Weyler
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Wilhelmus J Kwanten
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Eveline L Dirinck
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium
| | - Sven M Francque
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Luisa Vonghia
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
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15
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Maricic I, Marrero I, Eguchi A, Nakamura R, Johnson CD, Dasgupta S, Hernandez CD, Nguyen PS, Swafford AD, Knight R, Feldstein AE, Loomba R, Kumar V. Differential Activation of Hepatic Invariant NKT Cell Subsets Plays a Key Role in Progression of Nonalcoholic Steatohepatitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:3017-3035. [PMID: 30322964 PMCID: PMC6219905 DOI: 10.4049/jimmunol.1800614] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
Innate immune mechanisms play an important role in inflammatory chronic liver diseases. In this study, we investigated the role of type I or invariant NKT (iNKT) cell subsets in the progression of nonalcoholic steatohepatitis (NASH). We used α-galactosylceramide/CD1d tetramers and clonotypic mAb together with intracytoplasmic cytokine staining to analyze iNKT cells in choline-deficient l-amino acid-defined (CDAA)-induced murine NASH model and in human PBMCs, respectively. Cytokine secretion of hepatic iNKT cells in CDAA-fed C57BL/6 mice altered from predominantly IL-17+ to IFN-γ+ and IL-4+ during NASH progression along with the downmodulation of TCR and NK1.1 expression. Importantly, steatosis, steatohepatitis, and fibrosis were dependent upon the presence of iNKT cells. Hepatic stellate cell activation and infiltration of neutrophils, Kupffer cells, and CD8+ T cells as well as expression of key proinflammatory and fibrogenic genes were significantly blunted in Jα18-/- mice and in C57BL/6 mice treated with an iNKT-inhibitory RAR-γ agonist. Gut microbial diversity was significantly impacted in Jα18-/- and in CDAA diet-fed mice. An increased frequency of CXCR3+IFN-γ+T-bet+ and IL-17A+ iNKT cells was found in PBMC from NASH patients in comparison with nonalcoholic fatty liver patients or healthy controls. Consistent with their in vivo activation, iNKT cells from NASH patients remained hyporesponsive to ex-vivo stimulation with α-galactosylceramide. Accumulation of plasmacytoid dendritic cells in both mice and NASH patients suggest their role in activation of iNKT cells. In summary, our findings indicate that the differential activation of iNKT cells play a key role in mediating diet-induced hepatic steatosis and fibrosis in mice and its potential involvement in NASH progression in humans.
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Affiliation(s)
- Igor Maricic
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Idania Marrero
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Akiko Eguchi
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Ryota Nakamura
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Casey D Johnson
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
| | - Suryasarathi Dasgupta
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Carolyn D Hernandez
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Phirum Sam Nguyen
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Austin D Swafford
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093; and
| | - Ariel E Feldstein
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093
- Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
- Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093
| | - Vipin Kumar
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093;
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093
- Nonalcoholic Fatty Liver Disease Research Center, University of California San Diego, La Jolla, CA 92093
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16
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Cai J, Xu M, Zhang X, Li H. Innate Immune Signaling in Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2018; 14:153-184. [PMID: 30230967 DOI: 10.1146/annurev-pathmechdis-012418-013003] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The physiological significance of innate immune signaling lies primarily in its role in host defense against invading pathogens. It is becoming increasingly clear that innate immune signaling also modulates the development of metabolic diseases, especially nonalcoholic fatty liver disease and cardiovascular diseases, which are characterized by chronic, low-grade inflammation due to a disarrangement of innate immune signaling. Notably, recent studies indicate that in addition to regulating canonical innate immune-mediated inflammatory responses (or immune-dependent signaling-induced responses), molecules of the innate immune system regulate pathophysiological responses in multiple organs during metabolic disturbances (termed immune-independent signaling-induced responses), including the disruption of metabolic homeostasis, tissue repair, and cell survival. In addition, emerging evidence from the study of immunometabolism indicates that the systemic metabolic status may have profound effects on cellular immune function and phenotypes through the alteration of cell-intrinsic metabolism. We summarize how the innate immune system interacts with metabolic disturbances to trigger immune-dependent and immune-independent pathogenesis in the context of nonalcoholic fatty liver disease, as representative of metabolic diseases, and cardiovascular diseases.
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Affiliation(s)
- Jingjing Cai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; .,Institute of Model Animals of Wuhan University, Wuhan 430072, China.,Basic Medical School, Wuhan University, Wuhan 430071, China.,Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Meng Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; .,Institute of Model Animals of Wuhan University, Wuhan 430072, China.,Basic Medical School, Wuhan University, Wuhan 430071, China
| | - Xiaojing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; .,Institute of Model Animals of Wuhan University, Wuhan 430072, China.,Basic Medical School, Wuhan University, Wuhan 430071, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; .,Institute of Model Animals of Wuhan University, Wuhan 430072, China.,Basic Medical School, Wuhan University, Wuhan 430071, China
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18
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Hines IN, Kremer M, Moore SM, Wheeler MD. Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice. Biol Res 2018; 51:5. [PMID: 29448959 PMCID: PMC5815252 DOI: 10.1186/s40659-018-0153-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 02/06/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). METHODS Wild type (wt) or PPARα-deficient (PPARα-/-) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization. RESULTS Ten and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα-/- mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα-/- splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. CONCLUSION Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.
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Affiliation(s)
- Ian N. Hines
- Department of Nutrition Science, College of Allied Health Sciences, East Carolina University, Health Sciences Bldg. Room 4165F, Greenville, NC 27834 USA
- Department of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA
| | - Michael Kremer
- Department of General Surgery, University of Ulm, Ulm, Germany
- Department of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA
| | - Sherri M. Moore
- Department of Nutrition Science, College of Allied Health Sciences, East Carolina University, Health Sciences Bldg. Room 4165F, Greenville, NC 27834 USA
| | - Michael D. Wheeler
- Department of Nutrition Science, College of Allied Health Sciences, East Carolina University, Health Sciences Bldg. Room 4165F, Greenville, NC 27834 USA
- Department of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA
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19
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Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Fatty Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:369-390.e14. [DOI: 10.1016/b978-0-323-37591-7.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients. Inflammation 2017; 39:1729-36. [PMID: 27423204 DOI: 10.1007/s10753-016-0407-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69(+) and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites.
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HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflamm Res 2017; 66:477-486. [PMID: 28285394 DOI: 10.1007/s00011-017-1029-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/15/2017] [Accepted: 02/17/2017] [Indexed: 12/13/2022] Open
Abstract
Over the course of time, Hepatitis C has become a universal health menace. Its deleterious effects on human liver encompass a lot of physiological, genetic as well as epigenetic alterations. Fatty liver (Hepatic steatosis) is an inflammation having multifactorial ancestries; one of them is HCV (steatohepatitis). HCV boosts several cellular pathways involving up-regulation of a number of cytokines. Current study reviews the regulation of some selective key cytokines during HCV infection, to help generate an improved understanding of their role. These cytokines, IL-1β, IL-6, TNF-α, and IFN-ϒ, are inflammatory markers of the body. These particular markers along with others help hepatocytes against viral infestation. However, recently, their association has been found in degradation of liver on the trail heading to non-alcoholic steatohepatitis (NASH). Consequently, the disturbance in their equilibrium has been repeatedly reported during HCV infection. Quite a number of findings are affirming their up-regulation. Although these cell markers are stimulated by hepatocytes as their standard protection mechanism, but modern studies have testified the paradoxical nature of this defense line. Nevertheless, direct molecular or epigenetic research is needed to question the actual molecular progressions and directions commanding liver to steatosis, cirrhosis, or eventually HCC (Hepatocellular Carcinoma).
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Ilan Y, Ben Ya'acov A, Shabbat Y, Gingis-Velitski S, Almon E, Shaaltiel Y. Oral administration of a non-absorbable plant cell-expressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis. World J Gastroenterol 2016; 22:8760-8769. [PMID: 27818591 PMCID: PMC5075550 DOI: 10.3748/wjg.v22.i39.8760] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/21/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model. METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant anti-tumor necrosis factor alpha fusion protein (PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS. RESULTS The orally administered non-absorbable PRX-106 was biologically active. Altered distribution of CD4+CD25+FoxP3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+FoxP3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+FoxP3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice. CONCLUSION Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.
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Abstract
Nonalcoholic steatohepatitis (NASH) has become a major cause of cirrhosis and liver-related deaths worldwide. NASH is strongly associated with obesity and the metabolic syndrome, conditions that cause lipid accumulation in hepatocytes (hepatic steatosis). It is not well understood why some, but not other, individuals with hepatic steatosis develop NASH. The factors that determine whether or not NASH progresses to cirrhosis are also unclear. This review summarizes key components of NASH pathogenesis and discusses how inherent and acquired variations in regulation of these processes impact the risk for NASH and NASH cirrhosis.
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Affiliation(s)
- Ayako Suzuki
- Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Anna Mae Diehl
- Division of Gastroenterology, School of Medicine, Duke University, Durham, North Carolina 27710;
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Giles DA, Moreno-Fernandez ME, Divanovic S. IL-17 Axis Driven Inflammation in Non-Alcoholic Fatty Liver Disease Progression. Curr Drug Targets 2016; 16:1315-23. [PMID: 26028039 DOI: 10.2174/1389450116666150531153627] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 05/25/2015] [Indexed: 02/08/2023]
Abstract
Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common chronic liver disease in the world, represents a spectrum of disorders that range from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. It is anticipated that NAFLD will soon surpass chronic hepatitis C infection as the leading cause for needing liver transplantation. Despite its clinical and public health significance no specific therapies are available. Although the etiology of NAFLD is multifactorial and remains largely enigmatic, it is well accepted that inflammation is a central component of NAFLD pathogenesis. Despite the significance, critical immune mediators, loci of immune activation, the immune signaling pathways and the mechanism(s) underlying disease progression remain incompletely understood. Recent findings have focused on the role of Interleukin 17 (IL-17) family of proinflammatory cytokines in obesity and pathogenesis of obesity-associated sequelae. Notably, obesity favors a Th17 bias and is associated with increased IL-17A expression in both humans and mice. Further, in mice, IL-17 axis has been implicated in regulation of both obesity and NAFLD pathogenesis. However, despite these recent advances several important questions require further evaluation including: the relevant cellular source of IL-17A production; the critical IL- 17RA-expressing cell type; the critical liver infiltrating immune cells; and the underlying cellular effector mechanisms. Addressing these questions may aid in the identification and development of novel therapeutic targets for prevention of inflammation- driven NAFLD progression.
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Affiliation(s)
| | | | - Senad Divanovic
- Division of Immunobiology Cincinnati Children's Hospital Medical Center TCHRF - Location S, Room #S.5.409 3333 Burnet Avenue Cincinnati, Ohio 45229-3039 U.S.A.
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Jager J, Aparicio-Vergara M, Aouadi M. Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells. J Intern Med 2016; 280:209-20. [PMID: 26864622 DOI: 10.1111/joim.12483] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Obesity, which affects 600 million adults worldwide, is a major risk factor for type 2 diabetes (T2D) and insulin resistance. Current therapies for these metabolic disorders include weight management by lifestyle intervention or bariatric surgery and pharmacological treatment with the aim of regulating blood glucose. Probably because of their short-term effectiveness, these therapies have not been able to stop the rapidly rising prevalence of T2D over the past decades, highlighting an urgent need to develop new therapeutic strategies. The role of immune cells, such as macrophages, in insulin resistance has been extensively studied. Major advances have been made to elucidate the role of adipose tissue macrophages in these pathogeneses. Recently, anti-inflammatory drugs have been suggested as an alternative treatment for T2D, and clinical trials of these agents are currently ongoing. In addition, results of previous clinical trials using antibodies against inflammatory cytokines, which showed modest effects, are now being rigorously re-evaluated. However, it is still unclear how liver macrophages [termed Kupffer cells (KCs)], which constitute the major source of macrophages in the body, contribute to the development of insulin resistance. In this review, we will discuss the present understanding of the role of liver immune cells in the development of insulin resistance. We will particularly focus on KCs, which could represent an attractive target for the treatment of metabolic diseases.
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Affiliation(s)
- J Jager
- Department of Medicine, KI/AZ Integrated CardioMetabolic Center, Karolinska Institutet at Karolinska University Hospital Huddinge, C2-84, S-141 86, Stockholm, Sweden
| | - M Aparicio-Vergara
- Department of Medicine, KI/AZ Integrated CardioMetabolic Center, Karolinska Institutet at Karolinska University Hospital Huddinge, C2-84, S-141 86, Stockholm, Sweden
| | - M Aouadi
- Department of Medicine, KI/AZ Integrated CardioMetabolic Center, Karolinska Institutet at Karolinska University Hospital Huddinge, C2-84, S-141 86, Stockholm, Sweden
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Abstract
The liver is an organ that has the largest amount of natural killer T(NKT) cells, which play critical roles in the pathogenesis of liver diseases. In this article, the authors summarize recent findings about the roles of NKT cells in liver injury, inflammation, fibrosis, regeneration and cancer. In brief, NKT cells accelerate liver injury by producing pro-inflammatory cytokines and directly killing hepatocytes. NKT cells are involved in complex roles in liver fibrogenesis. For instance, NKT cells inhibit liver fibrosis via suppressing hepatic stellate cell activation and can also promote liver fibrosis via enhancing liver inflammation and injury. Inactivated or weakly activated NKT cells play a minimal role in controlling liver regeneration, whilst activated NKT cells have an inhibitory effect on liver regeneration. In liver cancer, NKT cells play both pro-tumor and anti-tumor roles in controlling tumor progress.
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Affiliation(s)
- Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
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27
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Hu Y, Zhang H, Li J, Cong X, Chen Y, He G, Chi Y, Liu Y. Gut-derived lymphocyte recruitment to liver and induce liver injury in non-alcoholic fatty liver disease mouse model. J Gastroenterol Hepatol 2016; 31:676-84. [PMID: 26430807 DOI: 10.1111/jgh.13183] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Revised: 08/12/2015] [Accepted: 08/31/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIM Most studies focus on gut-derived factors like microbiota and its products and how they contribute to non-alcoholic fatty liver disease (NAFLD) progression. This study investigated whether the gut-derived lymphocytes could migrate to the liver and induce liver injury in NAFLD. METHODS A high-fat diet induced an NAFLD mouse model, and lymphocytes were labeled with 1,1-dioctadecyl-3,3,3,3 tetramethylindotricarbocyanine iodide and carboxy-fluorescein succinimidyl ester, respectively, and intravenously injected to mice to monitor lymphocyte migration. RESULTS Adoptive transfer model results indicated that compared with lymphocytes from the spleen, bone marrow and thymus of NAFLD donor mice, mesenteric lymph nodes (MLN) cells from NAFLD donor mice predominately accumulated in the livers of NAFLD recipient mice. The frequencies of central memory CD4(+) T and CD8(+) T cells in livers of NAFLD mice were significantly increased; however, the activated T cells were not significantly altered. After adoptively transferred MLN cells, the frequencies of the activated CD4(+) T and CD8(+) T cells increased in livers of NAFLD recipient mice. By contrast, the frequencies of central memory and naïve CD4(+) T and CD8(+) T cells decreased. MLN cells also induced liver injury in NAFLD recipient mice, as reflected by elevated serum alanine aminotransferase and glutamic oxaloacetic transaminase serums. Moreover, the chemotaxis assay showed that CCL5 mediated the MLN cell migration to the liver. Also, blocking the CCL5 inhibited MLN cell migration to the liver in vitro. CONCLUSIONS Gut-derived lymphocytes from NAFLD mice could migrate to the liver and induce liver injury and hepatic CD4(+) T and CD8(+) T cells activation. The migration was associated with the upregulation of CCL5 in the liver.
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Affiliation(s)
- Ying Hu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
| | - Henghui Zhang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Jing Li
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
| | - Xu Cong
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Yanhui Chen
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Gaixia He
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Yujing Chi
- Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
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Lee SR, Park YK, Shin BA, Park HR. Effects of tumor vaccine expressing Granulocyte-Macrophage Colony Stimulating Factor and interleukin-18 fusion on cancer cells and its possible application for cancer immunotherapy. Cytokine 2016; 89:143-154. [PMID: 26868088 DOI: 10.1016/j.cyto.2016.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 01/15/2016] [Accepted: 01/19/2016] [Indexed: 11/19/2022]
Abstract
To access antitumor effects of a combined Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and interleukin-18 (IL-18), cDNA fusion of murine GM-CSF and mature IL-18 (GMIL-18) was constructed and transfected in mammalian cells. GMIL-18 fusion protein was highly secreted and displayed bifunctional activities, possessing immune response initiation and cytokine roles, including IFN-γ induction in mouse splenocytes and increased proliferation of GM-CSF-dependent cells, M-NSF-60. The GMIL-18 secreting tumor vaccine was generated and it strongly stimulated differentiation of dendrite cells (DCs) and effusive CD8+ and CD4+ cell infiltration into tumor mice. Moreover, growth of CT26 mouse colon cancer cells was significantly retarded by GMIL-18 (CT26GMIL-18), but not by CT26GM-CSF- or CT26IL-18. The efficiency of prophylactic vaccination was greater than that of therapeutic vaccination in terms of tumor size and its inhibitory role in proliferation. In micrometastasis analysis of tumor models, γ-ray irradiated GMIL-18 tumor vaccine showed a smaller number of liver-meta tumor nodules in mouse liver cells. We concluded that bifunctional GMIL-18 fusion protein could be applied as an immune therapy for cancer treatments.
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Affiliation(s)
- Sang Rok Lee
- Department of Molecular Medicine, Chonnam National University, Gwangju 501-757, Republic of Korea
| | - Young Kyu Park
- Department of Surgery, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea
| | - Boo Ahn Shin
- Deprtment of Microbiology, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea
| | - Hae-Ryoung Park
- Division of Liberal Arts & Teacher Training, Kwangju Women's University, Gwangju 506-713, Republic of Korea.
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29
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Cepero-Donates Y, Lacraz G, Ghobadi F, Rakotoarivelo V, Orkhis S, Mayhue M, Chen YG, Rola-Pleszczynski M, Menendez A, Ilangumaran S, Ramanathan S. Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease. Cytokine 2016; 82:102-11. [PMID: 26868085 DOI: 10.1016/j.cyto.2016.01.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Revised: 01/26/2016] [Accepted: 01/27/2016] [Indexed: 01/23/2023]
Abstract
Interleukin-15 (IL-15) is essential for the homeostasis of lymphoid cells particularly memory CD8(+) T cells and NK cells. These cells are abundant in the liver, and are implicated in obesity-associated pathogenic processes. Here we characterized obesity-associated metabolic and cellular changes in the liver of mice lacking IL-15 or IL-15Rα. High fat diet-induced accumulation of lipids was diminished in the livers of mice deficient for IL-15 or IL-15Rα. Expression of enzymes involved in the transport of lipids in the liver showed modest differences. More strikingly, the liver tissues of IL15-KO and IL15Rα-KO mice showed decreased expression of chemokines CCl2, CCL5 and CXCL10 and reduced infiltration of mononuclear cells. In vitro, IL-15 stimulation induced chemokine gene expression in wildtype hepatocytes, but not in IL15Rα-deficient hepatocytes. Our results show that IL-15 is implicated in the high fat diet-induced lipid accumulation and inflammation in the liver, leading to fatty liver disease.
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Affiliation(s)
- Yuneivy Cepero-Donates
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Grégory Lacraz
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada; Hubrecht Institute, University Medical Center, Utrecht, The Netherlands
| | - Farnaz Ghobadi
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Volatiana Rakotoarivelo
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Sakina Orkhis
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Marian Mayhue
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Yi-Guang Chen
- Department of Pediatrics, Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, USA
| | - Marek Rola-Pleszczynski
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada; CRCHUS, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Alfredo Menendez
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada; CRCHUS, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Subburaj Ilangumaran
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada; CRCHUS, Sherbrooke, Québec, QC J1H 5N4, Canada
| | - Sheela Ramanathan
- Division of Immunology, Departments of Pediatrics, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada; CRCHUS, Sherbrooke, Québec, QC J1H 5N4, Canada.
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30
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Ferrere G, Leroux A, Wrzosek L, Puchois V, Gaudin F, Ciocan D, Renoud ML, Naveau S, Perlemuter G, Cassard AM. Activation of Kupffer Cells Is Associated with a Specific Dysbiosis Induced by Fructose or High Fat Diet in Mice. PLoS One 2016; 11:e0146177. [PMID: 26731543 PMCID: PMC4701447 DOI: 10.1371/journal.pone.0146177] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 12/13/2015] [Indexed: 12/29/2022] Open
Abstract
The increase consumption of fructose in diet is associated with liver inflammation. As a specific fructan substrate, fructose may modify the gut microbiota which is involved in obesity-induced liver disease. Here, we aimed to assess whether fructose-induced liver damage was associated with a specific dysbiosis, especially in mice fed a high fat diet (HFD). To this end, four groups of mice were fed with normal and HFD added or not with fructose. Body weight and glucose sensitivity, liver inflammation, dysbiosis and the phenotype of Kupffer cells were determined after 16 weeks of diet. Food intake was increased in the two groups of mice fed with the HFD. Mice fed with HFD and fructose showed a higher infiltration of lymphocytes into the liver and a lower inflammatory profile of Kupffer cells than mice fed with the HFD without fructose. The dysbiosis associated with diets showed that fructose specifically prevented the decrease of Mouse intestinal bacteria in HFD fed mice and increased Erysipelotrichi in mice fed with fructose, independently of the amount of fat. In conclusion, fructose, used as a sweetener, induced a dysbiosis which is different in presence of fat in the diet. Consequently, the activation of Kupffer cells involved in mice model of HFD-induced liver inflammation was not observed in an HFD/fructose combined diet. These data highlight that the complexity of diet composition could highly impact the development of liver lesions during obesity. Specific dysbiosis associated with the diet could explain that the progressions of liver damage are different.
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Affiliation(s)
- Gladys Ferrere
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
| | - Anne Leroux
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
| | - Laura Wrzosek
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
| | - Virginie Puchois
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
| | - Françoise Gaudin
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- IPSIT, IFR141, Clamart, 92140, France
| | - Dragos Ciocan
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
- AP-HP, Hôpital Antoine Béclère, Service d’hépato-gastroentérologie, Clamart, 92140, France
| | - Marie-Laure Renoud
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
| | - Sylvie Naveau
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
- AP-HP, Hôpital Antoine Béclère, Service d’hépato-gastroentérologie, Clamart, 92140, France
| | - Gabriel Perlemuter
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
- AP-HP, Hôpital Antoine Béclère, Service d’hépato-gastroentérologie, Clamart, 92140, France
| | - Anne-Marie Cassard
- UMR996 - Inflammation, Chemokines and Immunopathology -, Inserm, Univ Paris-Sud, Université Paris-Saclay, 92140, Clamart, France
- Univ Paris-Sud, DHU Hepatinov, Labex LERMIT, Clamart, 92140, France
- * E-mail:
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Rau M, Schilling AK, Meertens J, Hering I, Weiss J, Jurowich C, Kudlich T, Hermanns HM, Bantel H, Beyersdorf N, Geier A. Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver. THE JOURNAL OF IMMUNOLOGY 2015; 196:97-105. [PMID: 26621860 DOI: 10.4049/jimmunol.1501175] [Citation(s) in RCA: 220] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 10/30/2015] [Indexed: 12/16/2022]
Abstract
Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4(+) effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4(+)CD45RA(+)CD25(++)) and higher frequencies of IFN-γ(+) and/or IL-4(+) cells were detected among CD4(+) T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17(+) cells among intrahepatic CD4(+) T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17(+) cells among intrahepatic CD4(+) T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.
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Affiliation(s)
- Monika Rau
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Anne-Kristin Schilling
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Jan Meertens
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Ilona Hering
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Johannes Weiss
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Christian Jurowich
- Department of General and Visceral Surgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Theodor Kudlich
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Heike M Hermanns
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; and
| | - Niklas Beyersdorf
- Institute for Virology and Immunobiology, University of Würzburg, 97080 Würzburg, Germany
| | - Andreas Geier
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
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Almeda-Valdes P, Aguilar Olivos NE, Barranco-Fragoso B, Uribe M, Méndez-Sánchez N. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease. BIOMED RESEARCH INTERNATIONAL 2015; 2015:768071. [PMID: 26339640 PMCID: PMC4538585 DOI: 10.1155/2015/768071] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 06/01/2015] [Accepted: 06/14/2015] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance.
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Affiliation(s)
- Paloma Almeda-Valdes
- Endocrinology and Metabolism Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14080 Mexico, DF, Mexico
| | | | - Beatriz Barranco-Fragoso
- Department of Gastroenterology, National Medical Center “20 Noviembre”, 03229 Mexico, DF, Mexico
| | - Misael Uribe
- Liver Research Unit, Medica Sur Clinic & Foundation, 14050 Mexico, DF, Mexico
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Vonghia L, Francque S. Cross talk of the immune system in the adipose tissue and the liver in non-alcoholic steatohepatitis: Pathology and beyond. World J Hepatol 2015; 7:1905-1912. [PMID: 26244065 PMCID: PMC4517150 DOI: 10.4254/wjh.v7.i15.1905] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 04/30/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is considered to be the hepatic manifestation of the metabolic syndrome, thus has a tight correlation with systemic metabolic impairment. The complex mechanisms underlying the pathogenesis of NASH involve different organs and systems that cross talk together contributing to the onset of NASH. A crucial role is played by inflammatory mediators, especially those deriving from the adipose tissue and the liver, which are involved in the cascade of inflammation, fibrosis and eventually tumorigenesis. In this setting cytokines and adipokines as well as immunity are emerging drivers of the key features of NASH. The immune system participates in this process with disturbances of the cells constituting both the innate and the adaptive immune systems that have been reported in different organs, such as in the liver and in the adipose tissue, in clinical and preclinical studies. The role of the immune system in NASH is increasingly studied, not only because of its contribution to the pathogenetic mechanisms of NASH but also because of the new potential therapeutic options it offers in this setting. Indeed, novel treatments acting on the immune system could offer new options in the management of NASH and the correlated clinical consequences.
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Hirsova P, Gores GJ. Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2014; 1:17-27. [PMID: 25729762 PMCID: PMC4340657 DOI: 10.1016/j.jcmgh.2014.11.005] [Citation(s) in RCA: 157] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming public health problem worldwide. A subset of patients develop an inflammatory disease, nonalcoholic steatohepatitis (NASH), characterized by steatosis, hepatocellular death, macrophage and neutrophil accumulation and varying stages of fibrosis. Hepatocyte cell death triggers the cellular inflammatory response and, therefore, reducing cell death may be salutary in the steatohepatitis disease process. Recently, a better understanding of hepatocyte apoptosis in NASH has been obtained and new information regarding other cell death modes, such as necroptosis and pyroptosis, has been reported. Hepatocyte lipotoxicity is often triggered by death receptors. In addition to causing apoptosis, death receptors have been shown to mediate proinflammatory signaling, suggesting that apoptosis in this context is not an immunologically silent process. Here we review recent developments in our understanding of hepatocyte cell death by death receptors and its mechanistic link to inflammation in NASH. We emphasize how proapoptotic signaling by death receptors may induce the release of proinflammatory extracellular vesicles, thereby recruiting and activating macrophages and promoting the steatohepatitis process. Potential therapeutic strategies are discussed based on this evolving information.
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Affiliation(s)
| | - Gregory J. Gores
- Correspondence Address correspondence to: Gregory J. Gores, MD, Professor of Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. fax: (507) 284-0762.
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Lazic M, Inzaugarat ME, Povero D, Zhao IC, Chen M, Nalbandian M, Miller YI, Cherñavsky AC, Feldstein AE, Sears DD. Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PLoS One 2014; 9:e107658. [PMID: 25251155 PMCID: PMC4175074 DOI: 10.1371/journal.pone.0107658] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 08/13/2014] [Indexed: 02/07/2023] Open
Abstract
Obesity is associated with metabolic perturbations including liver and adipose tissue inflammation, insulin resistance, and type 2 diabetes. Omega-6 fatty acids (ω6) promote and omega-3 fatty acids (ω3) reduce inflammation as they can be metabolized to pro- and anti-inflammatory eicosanoids, respectively. 12/15-lipoxygenase (12/15-LO) enzymatically produces some of these metabolites and is induced by high fat (HF) diet. We investigated the effects of altering dietary ω6/ω3 ratio and 12/15-LO deficiency on HF diet-induced tissue inflammation and insulin resistance. We examined how these conditions affect circulating concentrations of oxidized metabolites of ω6 arachidonic and linoleic acids and innate and adaptive immune system activity in the liver. For 15 weeks, wild-type (WT) mice were fed either a soybean oil-enriched HF diet with high dietary ω6/ω3 ratio (11∶1, HFH), similar to Western-style diet, or a fat Kcal-matched, fish oil-enriched HF diet with a low dietary ω6/ω3 ratio of 2.7∶1 (HFL). Importantly, the total saturated, monounsaturated and polyunsaturated fat content was matched in the two HF diets, which is unlike most published fish oil studies in mice. Despite modestly increased food intake, WT mice fed HFL were protected from HFH-diet induced steatohepatitis, evidenced by decreased hepatic mRNA expression of pro-inflammatory genes and genes involved in lymphocyte homing, and reduced deposition of hepatic triglyceride. Furthermore, oxidized metabolites of ω6 arachidonic acid were decreased in the plasma of WT HFL compared to WT HFH-fed mice. 12/15-LO knockout (KO) mice were also protected from HFH-induced fatty liver and elevated mRNA markers of inflammation and lymphocyte homing. 12/15-LOKO mice were protected from HFH-induced insulin resistance but reducing dietary ω6/ω3 ratio in WT mice did not ameliorate insulin resistance or adipose tissue inflammation. In conclusion, lowering dietary ω6/ω3 ratio in HF diet significantly reduces steatohepatitis.
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Affiliation(s)
- Milos Lazic
- Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America
| | | | - Davide Povero
- Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America
| | - Iris C. Zhao
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
| | - Mark Chen
- Department of Medicine, University of California San Diego, La Jolla, California, United States of America
| | - Madlena Nalbandian
- Department of Medicine, University of California San Diego, La Jolla, California, United States of America
| | - Yury I. Miller
- Department of Medicine, University of California San Diego, La Jolla, California, United States of America
| | | | - Ariel E. Feldstein
- Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America
| | - Dorothy D. Sears
- Department of Medicine, University of California San Diego, La Jolla, California, United States of America
- * E-mail:
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Resveratrol- and melatonin-abated ovariectomy and fructose diet–induced obesity and metabolic alterations in female rats. Menopause 2014; 21:876-85. [DOI: 10.1097/gme.0000000000000187] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Wang X, Jiang Z, Xing M, Fu J, Su Y, Sun L, Zhang L. Interleukin-17 mediates triptolide-induced liver injury in mice. Food Chem Toxicol 2014; 71:33-41. [PMID: 24949944 DOI: 10.1016/j.fct.2014.06.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/05/2014] [Accepted: 06/06/2014] [Indexed: 01/30/2023]
Abstract
Triptolide (TP)-induced liver injury can be attributed to the Th17/Treg imbalance with the enhancement of the expansion of Th17 cells and suppression of the production of Tregs, especially the significant increase of interleukin (IL)-17 secreted by helper T (Th) 17 cells. To further investigate the involvement of IL-17-mediated immune response in the TP-induced hepatotoxicity, we examined the plasma transaminase, histopathological changes, hepatic frequencies of Th17 cells, hepatic expression of transcriptional factors and cytokines genes and plasma IL-17 levels after administration of TP (600 μg/kg) by oral gavage to female C57BL/6 mice. Mice treated with TP displayed acute liver injury with significantly increased hepatic frequencies of Th17 cells, mRNA expression of retinoid-related orphan receptor (ROR)-γt and plasma IL-17 level as well as the plasma ALT and AST. Neutralization study using anti-IL-17 antibody ameliorated TP-induced liver injury. In contrast, when challenged by coadministration of recombinant IL-17, hepatotoxicity was exacerbated in the triptolide-administered mice. In summary, this report was demonstrated for the first time that IL-17-mediated immune response is involved in the pathogenesis of TP-induced liver injury in mice, which may shed light on the mechanisms of TP-induced liver injury.
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Affiliation(s)
- Xinzhi Wang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Zhenzhou Jiang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, 24 Tong Jia Xiang, Nanjing 210009, PR China.
| | - Mengtao Xing
- Department of Pathology, University of Illinois at Chicago, 909 S. Wolcott St., Chicago, IL 60612, United States
| | - Jing Fu
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Yuwen Su
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; School of Pharmacy, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China
| | - Lixin Sun
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Luyong Zhang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Provincial Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China.
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Martin-Murphy BV, You Q, Wang H, De La Houssaye BA, Reilly TP, Friedman JE, Ju C. Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS One 2014; 9:e80949. [PMID: 24465369 PMCID: PMC3896335 DOI: 10.1371/journal.pone.0080949] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 10/14/2013] [Indexed: 12/12/2022] Open
Abstract
Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD). Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT) cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d−/− mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD) feeding. Compared with their WT counterparts, CD1d−/− mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d−/− mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health.
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Affiliation(s)
- Brittany V. Martin-Murphy
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Qiang You
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Hong Wang
- Division of Endocrinology, Diabetes & Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Becky A. De La Houssaye
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Timothy P. Reilly
- Drug Safety Evaluation, Research & Development, Bristol-Myers Squibb Company, Princeton, New Jersey, United States of America
| | - Jacob E. Friedman
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Cynthia Ju
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
- * E-mail:
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Wang X, Jiang Z, Cao W, Yuan Z, Sun L, Zhang L. Th17/Treg imbalance in triptolide-induced liver injury. Fitoterapia 2014; 93:245-51. [PMID: 24444892 DOI: 10.1016/j.fitote.2014.01.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/01/2014] [Accepted: 01/09/2014] [Indexed: 02/07/2023]
Abstract
The study was designed to investigate the immune-modulatory effects of triptolide (TP) on CD4(+) T cell responses during liver injury. Previous studies have suggested that TP plays a critical role in modulating both innate and adaptive immune reactions, but its effects on the Th17/Treg balance during TP-induced liver injury remain unknown. In this study, female C57BL/6 mice were administered by oral gavage with TP at a dose of 250 or 500 μg/kg per mouse. We examined the plasma biochemical parameters, histopathological changes, hepatic frequencies of Th17 cells and Treg cells, hepatic expression of transcriptional factors and cytokine genes and hepatic interleukin (IL)-17 and IL-10 levels in TP-administered mice. Mice treated with TP displayed liver injury with markedly increased plasma transaminase as well as hepatic mRNA expression of retinoid related orphan receptor (ROR)-γt and hepatic IL-17 level at 24h. However, hepatic frequencies of Tregs and hepatic expression of forkhead/winged-helix family transcriptional repressor p3 (FoxP3) decreased at 24h after TP administration. Furthermore, we found that elevated serum biochemical parameters positively correlated with the Th17/Treg ratios. Taken together, these results revealed a novel and interesting phenomenon of TP in the enhancement of the expansion of Th17 cells and suppression of the production of Tregs during liver injury, which may represent a new pathogenesis of TP-induced liver injury.
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Affiliation(s)
- Xinzhi Wang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Zhenzhou Jiang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Weiping Cao
- The Center Laboratory of Medicine, Maternity and Child Health Hospital, Zhenjiang 212001, PR China
| | - Ziqiao Yuan
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - LiXin Sun
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Luyong Zhang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Provincial Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China.
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Venken K, Seeuws S, Zabeau L, Jacques P, Decruy T, Coudenys J, Verheugen E, Windels F, Catteeuw D, Drennan M, Van Calenbergh S, Lambrecht BN, Yoshimura A, Tavernier J, Elewaut D. A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis. J Hepatol 2014; 60:175-82. [PMID: 23973929 DOI: 10.1016/j.jhep.2013.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 07/26/2013] [Accepted: 08/05/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells. METHODS The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice. RESULTS The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin. CONCLUSIONS Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.
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Affiliation(s)
- Koen Venken
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Sylvie Seeuws
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Lennart Zabeau
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium
| | - Peggy Jacques
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Tine Decruy
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Julie Coudenys
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Eveline Verheugen
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Fien Windels
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Dominiek Catteeuw
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium
| | - Michael Drennan
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Serge Van Calenbergh
- Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium
| | - Bart N Lambrecht
- Laboratory of Immunoregulation and Mucosal Immunology, Department of Molecular Biomedical Research, VIB and Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan
| | - Jan Tavernier
- Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium
| | - Dirk Elewaut
- Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
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Dowds CM, Kornell SC, Blumberg RS, Zeissig S. Lipid antigens in immunity. Biol Chem 2014; 395:61-81. [PMID: 23999493 PMCID: PMC4128234 DOI: 10.1515/hsz-2013-0220] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Accepted: 08/27/2013] [Indexed: 02/07/2023]
Abstract
Lipids are not only a central part of human metabolism but also play diverse and critical roles in the immune system. As such, they can act as ligands of lipid-activated nuclear receptors, control inflammatory signaling through bioactive lipids such as prostaglandins, leukotrienes, lipoxins, resolvins, and protectins, and modulate immunity as intracellular phospholipid- or sphingolipid-derived signaling mediators. In addition, lipids can serve as antigens and regulate immunity through the activation of lipid-reactive T cells, which is the topic of this review. We will provide an overview of the mechanisms of lipid antigen presentation, the biology of lipid-reactive T cells, and their contribution to immunity.
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Affiliation(s)
- C. Marie Dowds
- Department of Internal Medicine I, University Medical Center
Schleswig-Holstein, Schittenhelmstraße 12, D-24105 Kiel,
Germany
| | - Sabin-Christin Kornell
- Department of Internal Medicine I, University Medical Center
Schleswig-Holstein, Schittenhelmstraße 12, D-24105 Kiel,
Germany
| | - Richard S. Blumberg
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham
and Women’s Hospital, Harvard Medical School, 75 Francis Street,
Boston, MA 02115, USA
| | - Sebastian Zeissig
- Department of Internal Medicine I, University Medical Center
Schleswig-Holstein, Schittenhelmstraße 12, D-24105 Kiel,
Germany
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42
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Microbiota and nonalcoholic steatohepatitis. Semin Immunopathol 2013; 36:115-32. [PMID: 24337650 DOI: 10.1007/s00281-013-0404-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 10/15/2013] [Indexed: 02/07/2023]
Abstract
The recent rise in obesity-related diseases, such as nonalcoholic fatty liver disease and its strong association with microbiota, has elicited interest in the underlying mechanisms of these pathologies. Experimental models have highlighted several mechanisms connecting microbiota to the development of liver dysfunction in nonalcoholic steatohepatitis (NASH) such as increased energy harvesting from the diet, small intestine bacterial overgrowth, modulation of the intestinal barrier by glucagon-like peptide-2 secretions, activation of innate immunity through the lipopolysaccharide-CD14 axis caused by obesity-induced leptin, periodontitis, and sterile inflammation. The manipulation of microbiota through probiotics, prebiotics, antibiotics, and periodontitis treatment yields encouraging results for the treatment of obesity, diabetes, and NASH, but data in humans is scarce.
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Abstract
Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of "programmed" necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.
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Affiliation(s)
- Maria Eugenia Guicciardi
- 1Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Vonghia L, Michielsen P, Francque S. Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 2013; 14:19867-90. [PMID: 24084730 PMCID: PMC3821591 DOI: 10.3390/ijms141019867] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/11/2013] [Accepted: 09/22/2013] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation and hepatocyte injury and constitutes hepatic manifestation of the metabolic syndrome. The pathogenesis of NASH is complex and implicates cross-talk between different metabolically active sites, such as liver and adipose tissue. Obesity is considered a chronic low-grade inflammatory state and the liver has been recognized as being an "immunological organ". The complex role of the immune system in the pathogenesis of NASH is currently raising great interest, also in view of the possible therapeutic potential of immunotherapy in NASH. This review focuses on the disturbances of the cells constituting the innate and adaptive immune system in the liver and in adipose tissue.
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Affiliation(s)
- Luisa Vonghia
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Wilrijkstraat 10, Edegem 2650, Belgium; E-Mails: (P.M.); (S.F.)
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Policlinico, Piazza Giulio Cesare, Bari 70100, Italy
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +32-3821-3323; Fax: +32-3821-4478
| | - Peter Michielsen
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Wilrijkstraat 10, Edegem 2650, Belgium; E-Mails: (P.M.); (S.F.)
| | - Sven Francque
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Wilrijkstraat 10, Edegem 2650, Belgium; E-Mails: (P.M.); (S.F.)
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Scalera A, Di Minno MND, Tarantino G. What does irritable bowel syndrome share with non-alcoholic fatty liver disease? World J Gastroenterol 2013; 19:5402-5420. [PMID: 24023483 PMCID: PMC3761093 DOI: 10.3748/wjg.v19.i33.5402] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 06/05/2013] [Accepted: 07/23/2013] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS) are two very common diseases in the general population. To date, there are no studies that highlight a direct link between NAFLD and IBS, but some recent reports have found an interesting correlation between obesity and IBS. A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD, leading to an increased cardiovascular risk, and IBS, leading to microbial dysbiosis, impaired intestinal barrier and altered intestinal motility. It is not known when considering local and systemic inflammation/immune system activation, which one has greater importance in NAFLD and IBS pathogenesis. Also, the nervous system is implicated. In fact, inflammation participates in the development of mood disorders, such as anxiety and depression, characteristics of obesity and consequently of NAFLD and, on the other hand, in intestinal hypersensitivity and dysmotility.
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Abstract
Although the pathological role of the immune system in several metabolic disorders, including type 1 diabetes mellitus (T1DM) and Addison's disease, has long been recognized and studied, only in the last decade has it become apparent that the immune system plays a broad and more subtle role in local and systemic metabolism. It is now apparent that the immune system monitors and responds to specific metabolic cues in both pathologic and non-pathologic settings through a set of processes dubbed immunometabolism. Expansion of adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering thermogenesis all lead to the recruitment and activation of immune cells in key metabolic tissues. The responses are complex and not completely defined, and indeed, as is typical of rapidly evolving research areas, there are some conflicting reports, especially related to the metabolic consequences of manipulation of immune function. However, what is clear is the consensus that metabolic processes, especially obesity and obesity-related complications, activate both the innate and adaptive arms of the immune system. Canonical immune processes consist of discrete steps: surveillance, recognition, effector action and resolution. Over the last decade evidence for each part of the immune response has been found at the intersection of the immune system with metabolism. Although evidence for immune surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus and pancreas, immune cell function has been most intensively studied and best understood in adipose tissue where studies continue to provide insights into the intersection of the metabolic and immune systems. Here we review the modulation of immune cell populations in adipose tissue and discuss regulatory processes implicated in controlling the interface between metabolism and immunologic function.
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Affiliation(s)
- A W Ferrante
- Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
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Mouralidarane A, Soeda J, Visconti-Pugmire C, Samuelsson AM, Pombo J, Maragkoudaki X, Butt A, Saraswati R, Novelli M, Fusai G, Poston L, Taylor PD, Oben JA. Maternal obesity programs offspring nonalcoholic fatty liver disease by innate immune dysfunction in mice. Hepatology 2013; 58:128-38. [PMID: 23315950 DOI: 10.1002/hep.26248] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 09/19/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED The global prevalence of obesity-induced liver disease (nonalcoholic fatty liver disease; NAFLD) is rising. Suggested causes include a role for in utero influences of maternal obesity compounded by the availability of energy-dense foods throughout postnatal life. Using a physiologically relevant model, we investigated the role of the innate immune system in liver injury induced by maternal obesity followed by a postnatal obesogenic diet. Female C57BL/6J mice were fed a standard or obesogenic diet before and throughout pregnancy and during lactation. Female offspring were weaned onto a standard or obesogenic diet at 3 weeks postpartum. Biochemical and histological indicators of dysmetabolism, NAFLD and fibrosis, analysis of profibrotic pathways, liver innate immune cells, and reactive oxygen species (ROS) were investigated at 3, 6, and 12 months. Female offspring exposed to a postweaning obesogenic diet (OffCon-OD) demonstrated evidence of liver injury, which was exacerbated by previous exposure to maternal obesity (OffOb-OD), as demonstrated by raised alanine aminotransferase, hepatic triglycerides, and hepatic expression of interleukin (IL)-6, tumor necrosis factor alpha, transforming growth factor beta, alpha smooth muscle actin, and collagen (P < 0.01). Histological evidence of hepatosteatosis and a more-robust NAFLD phenotype with hepatic fibrosis was observed at 12 months in OffOb-OD. A role for the innate immune system was indicated by increased Kupffer cell numbers with impaired phagocytic function and raised ROS synthesis (P < 0.01), together with reduced natural killer T cells and raised interleukin (IL)-12 and IL-18. CONCLUSION Maternal obesity in the context of a postnatal hypercalorific obesogenic diet aggressively programs offspring NAFLD associated with innate immune dysfunction, resulting in a comprehensive phenotype that accurately reflects the human disease.
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Affiliation(s)
- Angelina Mouralidarane
- University College London, Institute of Liver and Digestive Health, Center for Fatty Liver and Repair-Regeneration Research, Royal Free Hospital, London, UK
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Abstract
Though the pharmaceutical industry's infatuation with the therapeutic potential of RNA interference (RNAi) technology has finally come down from its initial lofty levels,[1] hope is by no means lost for the once-burgeoning enterprise, as recent clinical trials are beginning to show efficacy in areas ranging from amyloidosis to hypercholesterolemia to muscular dystrophy. With such resurgence comes a more informed perspective on the needs of such therapeutics: a renewed focus on true RNA drug development, and a desire for enhanced site-specific delivery.[2] In this review, we will discuss the latter with regard to hepatic targeting by synthetic vectors, covering the implications of organ and cellular physiology on conjugate structure, particle morphology, and active targeting. In presenting efficacy in a variety of disease models, we emphasize as well the extraordinary degree to which synthetic formulation improves upon and coordinates efforts with oligonucleotide development. Such advances in the understanding of and the technology behind RNAi have the potential to finally stabilize the long-term prospects RNA therapeutic development.
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Abstract
Metabolic syndrome, obesity, and nonalcoholic steatohepatitis are associated with a state of chronic inflammation. The immune system and the inflammatory cascade can be involved in the development of any of the above common conditions. This association raises the question of whether immune therapy can be used for the treatment of nonalcoholic steatohepatitis. Although immune therapy is not yet feasible for clinical use, here, we review some of the recent data on the potential role of the various arms of the immune system in the development of nonalcoholic steatohepatitis and several potential therapeutic targets.
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Martin-Murphy BV, Kominsky DJ, Orlicky DJ, Donohue TM, Ju C. Increased susceptibility of natural killer T-cell-deficient mice to acetaminophen-induced liver injury. Hepatology 2013; 57:1575-84. [PMID: 23150232 PMCID: PMC3622784 DOI: 10.1002/hep.26134] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 10/18/2012] [Accepted: 10/23/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED Acetaminophen (APAP) overdose causes severe, fulminant liver injury. The underlying mechanism of APAP-induced liver injury (AILI), studied by a murine model, displays similar characteristics of injury as those observed in patients. Previous studies suggest that aside from APAP-induced direct damage to hepatocytes, the hepatic innate immune system is activated and may contribute to the overall pathogenesis of AILI. The current study employed the use of two murine natural killer (NK) cells with T-cell receptor (NKT) cell knockout models (CD1d(-/-) and Jα18(-/-) ) to elucidate the specific role of NKT cells in AILI. Compared to wild-type (WT) mice, NKT cell-deficient mice were more susceptible to AILI, as indicated by higher serum alanine transaminase levels and mortality. Increased levels of cytochrome P450 2E1 (CYP2E1) protein expression and activities, which resulted in increased APAP protein adduct formation, were observed in livers of APAP-treated NKT cell-deficient mice, compared to WT mice. Compared to WT mice, starvation of NKT cell-deficient mice induced a higher increase of ketone bodies, which up-regulate CYP2E1 through protein stabilization. CONCLUSION Our data revealed a novel role of NKT cells in regulating responses to starvation-induced metabolic stress. Elevated ketone body production in NKT cell-deficient mice resulted in increased CYP2E1-mediated APAP biotransformation and susceptibility to AILI.
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Affiliation(s)
| | - Douglas J. Kominsky
- Department of Anesthesiology and Perioperative Medicine and Mucosal Inflammation Program, Aurora, Colorado, USA, 80045
| | - David J. Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA, 80045
| | - Terrence M. Donohue
- Department of Veterans Affairs, VA Nebraska-Western Iowa Health Care System and Department of Internal Medicine, University of Nebraska, Omaha, Nebraska, 68105
| | - Cynthia Ju
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA, 80045,Integrated Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA, 80045,Address correspondence to: Cynthia Ju, Skaggs School of Pharmacy, UCAMC, C238, 12850 E. Montview Blvd. Aurora, CO 80045.
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