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Pessenda G, Ferreira TR, Paun A, Kabat J, Amaral EP, Kamenyeva O, Gazzinelli-Guimaraes PH, Perera SR, Ganesan S, Lee SH, Sacks DL. Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis. Nat Commun 2025; 16:3125. [PMID: 40169598 PMCID: PMC11961706 DOI: 10.1038/s41467-025-58360-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 03/19/2025] [Indexed: 04/03/2025] Open
Abstract
In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2-/- mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL.
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Affiliation(s)
- Gabriela Pessenda
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Tiago R Ferreira
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andrea Paun
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Juraj Kabat
- Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Eduardo P Amaral
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Olena Kamenyeva
- Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pedro Henrique Gazzinelli-Guimaraes
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Department of Microbiology, Immunology & Tropical Medicine School of Medicine & Health Sciences. The George Washington University, Washington DC, USA
| | - Shehan R Perera
- Department of Electrical and Computer Engineering, The Ohio State University, Columbus, OH, USA
| | - Sundar Ganesan
- Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sang Hun Lee
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David L Sacks
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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2
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Ramirez CFA, Akkari L. Myeloid cell path to malignancy: insights into liver cancer. Trends Cancer 2025:S2405-8033(25)00054-8. [PMID: 40140328 DOI: 10.1016/j.trecan.2025.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/12/2025] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
Clinically approved treatments for advanced liver cancer often lack potency because of the heterogeneous characteristics of hepatocellular carcinoma (HCC). This complexity is largely driven by context-dependent inflammatory responses brought on by diverse etiologies, such as metabolic dysfunction-associated steatohepatitis (MASH), the genetic makeup of cancer cells, and the versatile adaptability of immune cells, such as myeloid cells. In this review, we discuss the evolutionary dynamics of the immune landscape, particularly that of liver-resident Kupffer cells (KCs), TREM2+, and SPP1+ macrophages with an active role during liver disease progression, which eventually fuels hepatocarcinogenesis. We highlight exploitable immunomodulatory avenues amenable to mitigate both the inherent pathological characteristics of liver cancers and the associated external factors that favor malignancy, paving a roadmap toward improving the management and therapeutic outcome for patients with HCC.
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Affiliation(s)
- Christel F A Ramirez
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Leila Akkari
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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3
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Dovhyi R, Dvukhriadkina A, Ostrovska K, Rudyk M, Verhovcova I, Vaivode K, Pjanova D, Ostapchenko L, Skivka L. Bacteriophage derived dsRNA induces polarized activation of alveolar macrophages from Balb/c and C57Bl/6 mice in vitro in sex- and age-dependent manner. Cell Immunol 2025; 408:104916. [PMID: 39787694 DOI: 10.1016/j.cellimm.2025.104916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/21/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Bacteriophage-derived dsRNA (bp-dsRNA), also known as Larifan, is a poly-functional and wide-spectrum antiviral medication with potent interferonogenic activity. In the lungs of golden Syrian hamsters infected with SARS-CoV-2, Larifan substantially reduces viral load and decreases infection-induced pathological lesion severity. Alveolar macrophages (AM) are key sentinel cells in the lung, which play an important role in antiviral innate immune responses and, at the same time, can trigger infection-associated hyper-inflammatory response. This study revealed that treatment with bp-dsRNA (Larifan) in vitro modulates the functional profile of AM from intact Balb/c and C57Bl/6 mice. The pattern of the drug response depends on the animal strain, age and sex. AM from Balb/c mice generated a weaker response to the preparation as compared to cells from C57Bl/6 mice. Most emphatic responses to the treatment with bf-dsRNA (Larifan) were registered in AM from old males of both BALB/c and C57BL/6 strains with the strongest in the latter. AM from old C57BL/6 females were less likely to be influenced by the preparation. In most cases, exposure to bf-dsRNA (Larifan) increased AM phagocytic activity and was more often accompanied by the stimulation of intracellular reactive oxygen species generation, than by its decrease. In most animal groups, treatment with bf-dsRNA (Larifan) did not affect significantly CD206 expression and down-regulated CD80 expression in AM. Taken together, our findings suggest that bf-dsRNA (Larifan) not so much stimulates the bivalent phenotype of AM, as restrains their hyper-inflammatory responses through the control of antigen-presentation while preserving functional signatures typical of patrolling tissue-resident macrophages.
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Affiliation(s)
- R Dovhyi
- Educational and Scientific Centre "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 2, Hlushkov Avenue, Kyiv 03022, Ukraine
| | - A Dvukhriadkina
- Educational and Scientific Centre "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 2, Hlushkov Avenue, Kyiv 03022, Ukraine
| | - K Ostrovska
- Educational and Scientific Centre "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 2, Hlushkov Avenue, Kyiv 03022, Ukraine
| | - M Rudyk
- Educational and Scientific Centre "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 2, Hlushkov Avenue, Kyiv 03022, Ukraine.
| | - Irina Verhovcova
- Latvian Biomedical Research and Study Centre, Rātsupītes Street 1, k-1, Riga LV-1067, Latvia
| | - Kristine Vaivode
- Latvian Biomedical Research and Study Centre, Rātsupītes Street 1, k-1, Riga LV-1067, Latvia
| | - D Pjanova
- Latvian Biomedical Research and Study Centre, Rātsupītes Street 1, k-1, Riga LV-1067, Latvia
| | - L Ostapchenko
- Educational and Scientific Centre "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 2, Hlushkov Avenue, Kyiv 03022, Ukraine
| | - L Skivka
- Educational and Scientific Centre "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 2, Hlushkov Avenue, Kyiv 03022, Ukraine
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4
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Shi Q, Xue C, Zeng Y, Chu Q, Jiang S, Zhang Y, Yuan X, Zhu D, Li L. PPARα agonist ameliorates cholestatic liver injury by regulating hepatic macrophage homeostasis. Int J Biol Macromol 2025; 287:138510. [PMID: 39647740 DOI: 10.1016/j.ijbiomac.2024.138510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/10/2024]
Abstract
Inflammatory response plays an essential role in the pathogenesis of cholestatic liver injury. PPARα agonists have been shown to regulate bile acid homeostasis and hepatic inflammation. However, the immunoregulatory mechanisms through which PPARα agonists ameliorate cholestatic liver injury remain unclear. In this study, surgical bile duct ligation was performed to establish a mouse model of cholestasis. Our study revealed that PPARα agonist alleviated cholestatic liver injury in mice by suppressing inflammatory response, reducing neutrophil infiltration, and promoting M2-like macrophage polarization. CyTOF analysis showed that PPARα agonist increased the proportion of anti-inflammatory F4/80hiCD44+MHCII- M2-like macrophages while decreasing the proportion of pro-inflammatory CD64+CX3CR1+CCR2hiVISTAhiCD172a+CD44hi M1-like MoMFs. Additionally, scRNA-seq indicated that PPARα agonist regulated the developmental trajectory and homeostasis of hepatic macrophages. Mechanistically, PPARα agonist may influence the expression of immune regulators in heterogeneous macrophages to exert protective effects against cholestasis. In addition, the CCL and MIF signaling pathways may participate in the communication among hepatic immune cells, including macrophages, neutrophils, natural killer cells, and dendritic cells, in response to the PPARα agonist. In conclusions, PPARα agonist alleviated cholestatic liver injury by attenuating the inflammatory response and restoring hepatic macrophage homeostasis. This study might enhance the understanding of the immunoregulatory mechanisms of PPARα agonists, providing promising therapeutic targets for cholestatic liver diseases.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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5
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Wang Q, Wei J, He J, Ming S, Li X, Huang X, Hong Z, Wu Y. HSP70 contributes to pathogenesis of fulminant hepatitis induced by coronavirus. Int Immunopharmacol 2024; 141:112963. [PMID: 39159560 DOI: 10.1016/j.intimp.2024.112963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/07/2024] [Accepted: 08/15/2024] [Indexed: 08/21/2024]
Abstract
Fulminant viral hepatitis (FH) represents a significant clinical challenge, with its pathogenesis not yet fully elucidated. Heat shock protein (HSP)70, a molecular chaperone protein with a broad range of cytoprotective functions, is upregulated in response to stress. However, the role of HSP70 in FH remains to be investigated. Notably, HSP70 expression is upregulated in the livers of coronavirus-infected mice and patients. Therefore, we investigated the mechanistic role of HSP70 in coronavirus-associated FH pathogenesis. FH was induced in HSP70-deficient (HSP70 KO) mice or in WT mice treated with the HSP70 inhibitor VER155008 when infected with the mouse hepatitis virus strain A59 (MHV-A59). MHV-A59-infected HSP70 KO mice exhibited significantly reduced liver damage and mortality. This effect was attributed to decreased infiltration of monocyte-macrophages and neutrophils in the liver of HSP70 KO mice, resulting in lower levels of inflammatory cytokines such as IL-1β, TNFα, and IL-6, and a reduced viral load. Moreover, treatment with the HSP70 inhibitor VER155008 protected mice from MHV-A59-induced liver damage and FH mortality. In summary, HSP70 promotes coronavirus-induced FH pathogenesis by enhancing the infiltration of monocyte-macrophages and neutrophils and promoting the secretion of inflammatory cytokines. Therefore, HSP70 is a potential therapeutic target in viral FH intervention.
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Affiliation(s)
- Qiaohua Wang
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Jiayou Wei
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Jianzhong He
- Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Siqi Ming
- Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai, Guangdong Province 519015, China
| | - Xingyu Li
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Xi Huang
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Zhongsi Hong
- Center of Infectious Disease, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
| | - Yongjian Wu
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
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6
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Han D, Ma Q, Ballar P, Zhang C, Dai M, Luo X, Gu J, Wei C, Guo P, Zeng L, Hu M, Jiang C, Liang Y, Wang Y, Hou C, Wang X, Feng L, Shen Y, Shen Y, Hu X, Liu J. Reprogramming tumor-associated macrophages and inhibiting tumor neovascularization by targeting MANF-HSF1-HSP70-1 pathway: An effective treatment for hepatocellular carcinoma. Acta Pharm Sin B 2024; 14:4396-4412. [PMID: 39525584 PMCID: PMC11544390 DOI: 10.1016/j.apsb.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/09/2024] [Accepted: 04/26/2024] [Indexed: 11/16/2024] Open
Abstract
In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1-HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization.
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Affiliation(s)
- Dan Han
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Qiannan Ma
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Petek Ballar
- Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir 35130, Turkey
| | - Chunyang Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Min Dai
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Xiaoyuan Luo
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Jiong Gu
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei 230061, China
| | - Chuansheng Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Panhui Guo
- Department of Gastroenterology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230061, China
| | - Lulu Zeng
- Department of Gastroenterology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230061, China
| | - Min Hu
- Department of Gastroenterology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230061, China
| | - Can Jiang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Yanyan Liang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Yanyan Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Chao Hou
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Xian Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Lijie Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Yujun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Xiangpeng Hu
- Department of Gastroenterology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230061, China
| | - Jun Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
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7
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Xie L, Wu B, Fan Y, Tao Y, Jiang X, Li Q, Zhu H, Wang H, Hu C. Fatty acid synthesis is indispensable for Kupffer cells to eliminate bacteria in ALD progression. Hepatol Commun 2024; 8:e0522. [PMID: 39185911 PMCID: PMC11357694 DOI: 10.1097/hc9.0000000000000522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/18/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Dysregulated fatty acid metabolism is closely linked to the development of alcohol-associated liver disease (ALD). KCs, which are resident macrophages in the liver, play a critical role in ALD pathogenesis. However, the effect of alcohol on fatty acid metabolism in KCs remains poorly understood. The current study aims to investigate fatty acid metabolism in KCs and its potential effect on ALD development. METHODS Wild-type C57BL/6 mice were fed a Lieber-DeCarli ethanol liquid diet for 3 days. Then, the liver injury and levels of intrahepatic bacteria were assessed. Next, we investigated the effects and underlying mechanisms of ethanol exposure on fatty acid metabolism and the phagocytosis of KCs, both in vivo and in vitro. Finally, we generated KCs-specific Fasn knockout and overexpression mice to evaluate the impact of FASN on the phagocytosis of KCs and ethanol-induced liver injury. RESULTS Using Bodipy493/503 to stain intracellular neutral lipids, we found significantly reduced lipid levels in KCs from mice fed an alcohol-containing diet for 3 days and in RAW264.7 macrophages exposed to ethanol. Mechanistically, alcohol exposure suppressed sterol regulatory element-binding protein 1 transcriptional activity, thereby inhibiting fatty acid synthase (FASN)-mediated de novo lipogenesis in macrophages both in vitro and in vivo. We show that genetic ablation and pharmacologic inhibition of FASN significantly impaired KC's ability to take up and eliminate bacteria. Conversely, KCs-specific Fasn overexpression reverses the impairment of macrophage phagocytosis caused by alcohol exposure. We also revealed that KCs-specific Fasn knockout augmented KCs apoptosis and exacerbated liver injury in mice fed an alcohol-containing diet for 3 days. CONCLUSIONS Our findings indicate the crucial role of de novo lipogenesis in maintaining effective KCs phagocytosis and suggest a therapeutic target for ALD based on fatty acid synthesis in KCs.
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Affiliation(s)
- Liuyu Xie
- Department of Clinical Laboratory, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, PR China
| | - Beng Wu
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yuanyuan Fan
- Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases, Anhui Medical University, Hefei, China
| | - Ye Tao
- Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases, Anhui Medical University, Hefei, China
| | - Xiaoyong Jiang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Qing Li
- Department of Clinical Laboratory, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, PR China
- Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, PR China
| | - Huaiping Zhu
- Department of Clinical Laboratory, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, PR China
| | - Hua Wang
- School of Pharmacy, Anhui Medical University, Hefei, China
- Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases, Anhui Medical University, Hefei, China
| | - Chaojie Hu
- Department of Clinical Laboratory, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, PR China
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8
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Pessenda G, Ferreira TR, Paun A, Kabat J, Amaral EP, Kamenyeva O, Gazzinelli-Guimaraes PH, Perera SR, Ganesan S, Hun Lee S, Sacks DL. Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.09.602717. [PMID: 39372777 PMCID: PMC11451627 DOI: 10.1101/2024.07.09.602717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
In murine models of visceral leishmaniasis (VL), parasitization of resident Kupffer cells (resKCs) is responsible for early growth of Leishmania infantum in the liver, which leads to granuloma formation and eventual parasite control. We employed the chronic VL model, and revealed an open niche established by KCs death and their migration outside of the sinusoids, resulting in their gradual replacement by monocyte-derived KCs (moKCs). While early granulomas were composed of resKCs, late granulomas were found outside of the sinusoids and contained resKC-derived macrophages, and monocyte-derived macrophages (momacs). ResKCs and moKCs within the sinusoids were identified as homeostatic/regulatory cells, while resKC-derived macrophages and momacs within late granulomas were pro-inflammatory. Despite the infection being largely confined to the resKC-derived macrophages, in the absence of monocyte recruitment, parasite control was strongly compromised. Macrophage heterogeneity, involving migration and reprogramming of resKCs, along with recruitment of monocyte-derived cells, is a hallmark of granuloma maturation and hepatic immunity in VL.
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Affiliation(s)
- Gabriela Pessenda
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tiago R. Ferreira
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Andrea Paun
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Juraj Kabat
- Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Eduardo P. Amaral
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Olena Kamenyeva
- Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Pedro Henrique Gazzinelli-Guimaraes
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shehan R. Perera
- Department of Electrical and Computer Engineering, The Ohio State University, Columbus, OH 43201, USA
| | - Sundar Ganesan
- Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sang Hun Lee
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - David L. Sacks
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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9
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Quaranta V, Ballarò C, Giannelli G. Macrophages Orchestrate the Liver Tumor Microenvironment. Cancers (Basel) 2024; 16:1772. [PMID: 38730724 PMCID: PMC11083142 DOI: 10.3390/cancers16091772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024] Open
Abstract
Liver cancer is one of the leading causes of cancer-related mortality. Hepatocellular carcinoma and cholangiocarcinoma are the most common types, and despite numerous advances, therapeutic options still remain poor for these cancer patients. Tumor development and progression strictly depend on a supportive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant immune cells population within a tumorigenic liver; they sustain cancer cells' growth and invasiveness, and their presence is correlated with a poor prognosis. Furthermore, TAM cross-talk with cells and components of the TME promotes immunosuppression, a desmoplastic response, and angiogenesis. In this review, we summarize the latest advances in understanding TAM heterogeneity and function, with a particular focus on TAM modulation of the TME. We also discuss the potential of targeting macrophage subpopulations and how this is now being exploited in current clinical trials for the treatment of liver cancer.
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Affiliation(s)
- Valeria Quaranta
- National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy (G.G.)
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10
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Ping D, Peng Y, Hu X, Liu C. Macrophage cytotherapy on liver cirrhosis. Front Pharmacol 2023; 14:1265935. [PMID: 38161689 PMCID: PMC10757375 DOI: 10.3389/fphar.2023.1265935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/04/2023] [Indexed: 01/03/2024] Open
Abstract
Macrophages, an essential cell population involved in mediating innate immunity in the host, play a crucial role on the development of hepatic cirrhosis. Extensive studies have highlighted the potential therapeutic benefits of macrophage therapy in treating hepatic cirrhosis. This review aims to provide a comprehensive overview of the various effects and underlying mechanisms associated with macrophage therapy in the context of hepatic cirrhosis.
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Affiliation(s)
- Dabing Ping
- Institute of Liver Diseases, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuan Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xudong Hu
- Department of Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, China
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11
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Zhang W, Liu K, Ren GM, Wang Y, Wang T, Liu X, Li DX, Xiao Y, Chen X, Li YT, Zhan YQ, Xiang SS, Chen H, Gao HY, Zhao K, Yu M, Ge CH, Li CY, Ge ZQ, Yang XM, Yin RH. BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury. Cell Death Dis 2023; 14:743. [PMID: 37968261 PMCID: PMC10651896 DOI: 10.1038/s41419-023-06268-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 11/17/2023]
Abstract
BRISC (BRCC3 isopeptidase complex) is a deubiquitinating enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1β, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.
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Affiliation(s)
- Wen Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China
| | - Kai Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Guang-Ming Ren
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yu Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Ting Wang
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, 100124, China
| | - Xian Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Dong-Xu Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
| | - Yang Xiao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xu Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ya-Ting Li
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, 100124, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Shen-Si Xiang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Hui-Ying Gao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ke Zhao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chang-Hui Ge
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Zhi-Qiang Ge
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
| | - Xiao-Ming Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Rong-Hua Yin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
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12
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Musrati MA, De Baetselier P, Movahedi K, Van Ginderachter JA. Ontogeny, functions and reprogramming of Kupffer cells upon infectious disease. Front Immunol 2023; 14:1238452. [PMID: 37691953 PMCID: PMC10485603 DOI: 10.3389/fimmu.2023.1238452] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 08/11/2023] [Indexed: 09/12/2023] Open
Abstract
The liver is a vital metabolic organ that also performs important immune-regulatory functions. In the context of infections, the liver represents a target site for various pathogens, while also having an outstanding capacity to filter the blood from pathogens and to contain infections. Pathogen scavenging by the liver is primarily performed by its large and heterogeneous macrophage population. The major liver-resident macrophage population is located within the hepatic microcirculation and is known as Kupffer cells (KCs). Although other minor macrophages reside in the liver as well, KCs remain the best characterized and are the best well-known hepatic macrophage population to be functionally involved in the clearance of infections. The response of KCs to pathogenic insults often governs the overall severity and outcome of infections on the host. Moreover, infections also impart long-lasting, and rarely studied changes to the KC pool. In this review, we discuss current knowledge on the biology and the various roles of liver macrophages during infections. In addition, we reflect on the potential of infection history to imprint long-lasting effects on macrophages, in particular liver macrophages.
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Affiliation(s)
- Mohamed Amer Musrati
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Patrick De Baetselier
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Kiavash Movahedi
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
- Lab of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jo A. Van Ginderachter
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
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13
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Teh YC, Chooi MY, Chong SZ. Behind the monocyte's mystique: uncovering their developmental trajectories and fates. DISCOVERY IMMUNOLOGY 2023; 2:kyad008. [PMID: 38567063 PMCID: PMC10917229 DOI: 10.1093/discim/kyad008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 05/11/2023] [Accepted: 07/17/2023] [Indexed: 04/04/2024]
Abstract
Monocytes are circulating myeloid cells that are derived from dedicated progenitors in the bone marrow. Originally thought of as mere precursors for the replacement of tissue macrophages, it is increasingly clear that monocytes execute distinct effector functions and may give rise to monocyte-derived cells with unique properties from tissue-resident macrophages. Recently, the advent of novel experimental approaches such as single-cell analysis and fate-mapping tools has uncovered an astonishing display of monocyte plasticity and heterogeneity, which we believe has emerged as a key theme in the field of monocyte biology in the last decade. Monocyte heterogeneity is now recognized to develop as early as the progenitor stage through specific imprinting mechanisms, giving rise to specialized effector cells in the tissue. At the same time, monocytes must overcome their susceptibility towards cellular death to persist as monocyte-derived cells in the tissues. Environmental signals that preserve their heterogenic phenotypes and govern their eventual fates remain incompletely understood. In this review, we will summarize recent advances on the developmental trajectory of monocytes and discuss emerging concepts that contributes to the burgeoning field of monocyte plasticity and heterogeneity.
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Affiliation(s)
- Ye Chean Teh
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Ming Yao Chooi
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
| | - Shu Zhen Chong
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
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14
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Hu XH, Chen L, Wu H, Tang YB, Zheng QM, Wei XY, Wei Q, Huang Q, Chen J, Xu X. Cell therapy in end-stage liver disease: replace and remodel. Stem Cell Res Ther 2023; 14:141. [PMID: 37231461 DOI: 10.1186/s13287-023-03370-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.
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Affiliation(s)
- Xin-Hao Hu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lan Chen
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Wu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Yang-Bo Tang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Qiu-Min Zheng
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xu-Yong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qi Huang
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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15
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Ito Y, Hosono K, Amano H. Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury. Front Cell Dev Biol 2023; 11:1171317. [PMID: 37082623 PMCID: PMC10112669 DOI: 10.3389/fcell.2023.1171317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023] Open
Abstract
The liver displays a remarkable regenerative capacity in response to acute liver injury. In addition to the proliferation of hepatocytes during liver regeneration, non-parenchymal cells, including liver macrophages, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) play critical roles in liver repair and regeneration. Liver ischemia–reperfusion injury (IRI) is a major cause of increased liver damage during liver resection, transplantation, and trauma. Impaired liver repair increases postoperative morbidity and mortality of patients who underwent liver surgery. Successful liver repair and regeneration after liver IRI requires coordinated interplay and synergic actions between hepatic resident cells and recruited cell components. However, the underlying mechanisms of liver repair after liver IRI are not well understood. Recent technological advances have revealed the heterogeneity of each liver cell component in the steady state and diseased livers. In this review, we describe the progress in the biology of liver non-parenchymal cells obtained from novel technological advances. We address the functional role of each cell component in response to liver IRI and the interactions between diverse immune repertoires and non-hematopoietic cell populations during the course of liver repair after liver IRI. We also discuss how these findings can help in the design of novel therapeutic approaches. Growing insights into the cellular interactions during liver IRI would enhance the pathology of liver IRI understanding comprehensively and further develop the strategies for improvement of liver repair.
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16
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Kim HH, Shim YR, Choi SE, Kim MH, Lee G, You HJ, Choi WM, Yang K, Ryu T, Kim K, Kim MJ, Woo C, Chung KPS, Hong SH, Eun HS, Kim SH, Ko G, Park JE, Gao B, Kim W, Jeong WI. Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease. Exp Mol Med 2023; 55:158-170. [PMID: 36631664 PMCID: PMC9898237 DOI: 10.1038/s12276-022-00921-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/26/2022] [Accepted: 11/18/2022] [Indexed: 01/13/2023] Open
Abstract
Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.
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Affiliation(s)
- Hee-Hoon Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Young-Ri Shim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Sung Eun Choi
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Myung-Ho Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea ,grid.32224.350000 0004 0386 9924Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, MA USA
| | - Giljae Lee
- grid.31501.360000 0004 0470 5905Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826 Republic of Korea
| | - Hyun Ju You
- grid.31501.360000 0004 0470 5905Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826 Republic of Korea
| | - Won-Mook Choi
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea ,grid.413967.e0000 0001 0842 2126Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505 Republic of Korea
| | - Keungmo Yang
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Tom Ryu
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Kyurae Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Min Jeong Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Chaerin Woo
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Katherine Po Sin Chung
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Song Hwa Hong
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Hyuk Soo Eun
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea ,grid.254230.20000 0001 0722 6377Department of Internal Medicine, Chungnam National University, College of Medicine, Daejeon, 35015 Republic of Korea
| | - Seok-Hwan Kim
- grid.254230.20000 0001 0722 6377Department of Surgery, Chungnam National University, College of Medicine, Daejeon, 35015 Republic of Korea
| | - GwangPyo Ko
- grid.31501.360000 0004 0470 5905Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826 Republic of Korea
| | - Jong-Eun Park
- grid.37172.300000 0001 2292 0500Single-Cell Medical Genomics Laboratory, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Bin Gao
- grid.420085.b0000 0004 0481 4802Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD 20892 USA
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, 07061, Republic of Korea.
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.
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17
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Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis. Cell Death Dis 2022; 13:1031. [PMID: 36494334 PMCID: PMC9734196 DOI: 10.1038/s41419-022-05487-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022]
Abstract
The cell-cell interaction between hepatocytes and Kupffer cells (KCs) is crucial for maintaining liver homeostasis, and the loss of KCs and hepatocytes is known to represent a common pathogenic phenomenon in autoimmune hepatitis. Until now, the mechanisms of cell-cell interaction between hepatocytes and KCs involved in immune-mediated hepatitis remains unclear. Here we dissected the impact of activated mTORC1 on the cell-cell interaction of KCs and hepatocyte in immune-mediated hepatitis. In the liver from patients with AIH and mice administrated with Con-A, mTORC1 was activated in both KCs and hepatocytes. The activated mTORC1 signal in hepatocytes with Con-A challenge caused a markedly production of miR-329-3p. Upregulated miR-329-3p inhibited SGMS1 expression in KCs through paracrine, resulting in the death of KCs. Most of maintained KCs were p-S6 positive and distributed in hepatocyte mTORC1 negative area. The activation of mTORC1 enabled KCs expressed complement factor B (CFB) to enhance the complement alternative system, which produced more complement factors to aggravate liver injury. Our findings remonstrate a heterogeneous role of mTORC1 in specific cell type for maintaining tolerogenic liver environment, and will form the basis for the development of new interventions against immune-mediated hepatitis.
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18
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Guilliams M, Scott CL. Liver macrophages in health and disease. Immunity 2022; 55:1515-1529. [PMID: 36103850 DOI: 10.1016/j.immuni.2022.08.002] [Citation(s) in RCA: 192] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 12/30/2022]
Abstract
Single-cell and spatial transcriptomic technologies have revealed an underappreciated heterogeneity of liver macrophages. This has led us to rethink the involvement of macrophages in liver homeostasis and disease. Identification of conserved gene signatures within these cells across species and diseases is enabling the correct identification of specific macrophage subsets and the generation of more specific tools to track and study the functions of these cells. Here, we discuss what is currently known about the definitions of these different macrophage populations, the markers that can be used to identify them, how they are wired within the liver, and their functional specializations in health and disease.
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Affiliation(s)
- Martin Guilliams
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium.
| | - Charlotte L Scott
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Chemical Sciences, Bernal Institute, University of Limerick, Castletroy, County Limerick, Ireland.
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19
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Soares GA, Pereira GM, Romualdo GR, Biasotti GGA, Stoppa EG, Bakuzis AF, Baffa O, Barbisan LF, Miranda JRA. Biodistribution Profile of Magnetic Nanoparticles in Cirrhosis-Associated Hepatocarcinogenesis in Rats by AC Biosusceptometry. Pharmaceutics 2022; 14:pharmaceutics14091907. [PMID: 36145654 PMCID: PMC9504370 DOI: 10.3390/pharmaceutics14091907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/30/2022] [Accepted: 08/31/2022] [Indexed: 11/20/2022] Open
Abstract
Since magnetic nanoparticles (MNPs) have been used as multifunctional probes to diagnose and treat liver diseases in recent years, this study aimed to assess how the condition of cirrhosis-associated hepatocarcinogenesis alters the biodistribution of hepatic MNPs. Using a real-time image acquisition approach, the distribution profile of MNPs after intravenous administration was monitored using an AC biosusceptometry (ACB) assay. We assessed the biodistribution profile based on the ACB images obtained through selected regions of interest (ROIs) in the heart and liver position according to the anatomical references previously selected. The signals obtained allowed for the quantification of pharmacokinetic parameters, indicating that the uptake of hepatic MNPs is compromised during liver cirrhosis, since scar tissue reduces blood flow through the liver and slows its processing function. Since liver monocytes/macrophages remained constant during the cirrhotic stage, the increased intrahepatic vascular resistance associated with impaired hepatic sinusoidal circulation was considered the potential reason for the change in the distribution of MNPs.
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Affiliation(s)
- Guilherme A. Soares
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
- Correspondence:
| | - Gabriele M. Pereira
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Guilherme R. Romualdo
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
- Department of Strucutral and Functional Biology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Gabriel G. A. Biasotti
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Erick G. Stoppa
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Andris F. Bakuzis
- Institute of Physics, Federal University of Goiás, Goiânia 74690-900, GO, Brazil
| | - Oswaldo Baffa
- Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-900, SP, Brazil
| | - Luis F. Barbisan
- Department of Strucutral and Functional Biology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Jose R. A. Miranda
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
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20
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Lopes ME, Nakagaki BN, Mattos MS, Campolina-Silva GH, Meira RDO, Paixão P, Oliveira A, Faustino L, Gonçalves R, Menezes GB. Susceptibility to Infections During Acute Liver Injury Depends on Transient Disruption of Liver Macrophage Niche. Front Immunol 2022; 13:892114. [PMID: 35967353 PMCID: PMC9368782 DOI: 10.3389/fimmu.2022.892114] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/20/2022] [Indexed: 11/25/2022] Open
Abstract
Kupffer cells are the primary liver resident immune cell responsible for the liver firewall function, including clearance of bacterial infection from the circulation, as they are strategically positioned inside the liver sinusoid with intimate contact with the blood. Disruption in the tissue-resident macrophage niche, such as in Kupffer cells, can lead to a window of susceptibility to systemic infections, which represents a significant cause of mortality in patients with acetaminophen (APAP) overdose-induced acute liver injury (ALI). However, how Kupffer cell niche disruption increases susceptibility to systemic infections in ALI is not fully understood. Using a mouse model of ALI induced by APAP overdose, we found that Kupffer cells upregulated the apoptotic cell death program and were markedly reduced in the necrotic areas during the early stages of ALI, opening the niche for the infiltration of neutrophils and monocyte subsets. In addition, during the resolution phase of ALI, the remaining tissue macrophages with a Kupffer cell morphology were observed forming replicating cell clusters closer to necrotic areas devoid of Kupffer cells. Interestingly, mice with APAP-induced liver injury were still susceptible to infections despite the dual cellular input of circulating monocytes and proliferation of remaining Kupffer cells in the damaged liver. Therapy with bone marrow-derived macrophages (BMDM) was shown to be effective in occupying the niche devoid of Kupffer cells following APAP-induced ALI. The rapid BMDM migration to the liver and their positioning within necrotic areas enhanced the healing of the tissue and restored the liver firewall function after BMDM therapy. Therefore, we showed that disruption in the Kupffer cell niche and its impaired function during acute liver injury are key factors for the susceptibility to systemic bacterial infections. In addition, modulation of the liver macrophage niche was shown to be a promising therapeutic strategy for liver injuries that reduce the Kupffer cell number and compromise the organ function.
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Affiliation(s)
- Mateus Eustáquio Lopes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
- *Correspondence: Mateus Eustáquio Lopes, ; Gustavo Batista Menezes,
| | - Brenda Naemi Nakagaki
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Matheus Silvério Mattos
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gabriel Henrique Campolina-Silva
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
- Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada
| | - Raquel de Oliveira Meira
- Macrophage and Monocyte Biology Laboratory, Department of Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Pierre Henrique de Menezes Paixão
- Macrophage and Monocyte Biology Laboratory, Department of Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - André Gustavo Oliveira
- Department of Physiology and Biophysics, Instituto de Ciências Biológicas, Universidade
Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Lucas D. Faustino
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Ricardo Gonçalves
- Macrophage and Monocyte Biology Laboratory, Department of Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gustavo Batista Menezes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
- *Correspondence: Mateus Eustáquio Lopes, ; Gustavo Batista Menezes,
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21
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Li W, Chang N, Li L. Heterogeneity and Function of Kupffer Cells in Liver Injury. Front Immunol 2022; 13:940867. [PMID: 35833135 PMCID: PMC9271789 DOI: 10.3389/fimmu.2022.940867] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022] Open
Abstract
Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.
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22
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Ander SE, Li FS, Carpentier KS, Morrison TE. Innate immune surveillance of the circulation: A review on the removal of circulating virions from the bloodstream. PLoS Pathog 2022; 18:e1010474. [PMID: 35511797 PMCID: PMC9070959 DOI: 10.1371/journal.ppat.1010474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Many viruses utilize the lymphohematogenous route for dissemination; however, they may not freely use this highway unchecked. The reticuloendothelial system (RES) is an innate defense system that surveys circulating blood, recognizing and capturing viral particles. Examination of the literature shows that the bulk of viral clearance is mediated by the liver; however, the precise mechanism(s) mediating viral vascular clearance vary between viruses and, in many cases, remains poorly defined. Herein, we summarize what is known regarding the recognition and capture of virions from the circulation prior to the generation of a specific antibody response. We also discuss the consequences of viral capture on viral pathogenesis and the fate of the captor cell. Finally, this understudied topic has implications beyond viral pathogenesis, including effects on arbovirus ecology and the application of virus-vectored gene therapies.
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Affiliation(s)
- Stephanie E. Ander
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Frances S. Li
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Kathryn S. Carpentier
- Department of Natural Sciences, Greensboro College, Greensboro, North Carolina, United States of America
| | - Thomas E. Morrison
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
- * E-mail:
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23
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Xiao F, Wang HW, Hu JJ, Tao R, Weng XX, Wang P, Wu D, Wang XJ, Yan WM, Xi D, Luo XP, Wan XY, Ning Q. Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation. World J Gastroenterol 2022; 28:479-496. [PMID: 35125831 PMCID: PMC8790557 DOI: 10.3748/wjg.v28.i4.479] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/18/2021] [Accepted: 01/08/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Heterogeneous macrophages play an important role in multiple liver diseases, including viral fulminant hepatitis (VFH). Fibrinogen-like protein 2 (FGL2) is expressed on macrophages and regulates VFH pathogenesis; however, the underlying mechanism remains unclear. AIM To explore how FGL2 regulates macrophage function and subsequent liver injury during VFH. METHODS Murine hepatitis virus strain 3 (MHV-3) was used to induce VFH in FGL2-deficient (Fgl2-/-) and wild-type (WT) mice. The dynamic constitution of hepatic macrophages was examined. Adoptive transfer of Fgl2-/- or WT bone marrow-derived macrophages (BMDMs) into WT recipients with macrophages depleted prior to infection was carried out and the consequent degree of liver damage was compared. The signaling cascades that may be regulated by FGL2 were detected in macrophages. RESULTS Following MHV-3 infection, hepatic macrophages were largely replenished by proinflammatory monocyte-derived macrophages (MoMFs), which expressed high levels of FGL2. In Fgl2-/- mice, the number of infiltrating inflammatory MoMFs was reduced compared with that in WT mice after viral infection. Macrophage depletion ameliorated liver damage in WT mice and further alleviated liver damage in Fgl2-/- mice. Adoptive transfer of Fgl2-/- BMDMs into macrophage-removed recipients significantly reduced the degree of liver damage. Inhibition of monocyte infiltration also significantly ameliorated liver damage. Functionally, Fgl2 deletion impaired macrophage phagocytosis and the antigen presentation potential and attenuated the proinflammatory phenotype. At the molecular level, FGL2 deficiency impaired IRF3, IRF7, and p38 phosphorylation, along with NF-κB activation in BMDMs in response to viral infection. CONCLUSION Infiltrated MoMFs represent a major source of hepatic inflammation during VFH progression, and FGL2 expression on MoMFs maintains the proinflammatory phenotype via p38-dependent positive feedback, contributing to VFH pathogenesis.
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Affiliation(s)
- Fang Xiao
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Province, China
| | - Hong-Wu Wang
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jun-Jian Hu
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Ran Tao
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xin-Xin Weng
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Peng Wang
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Di Wu
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xiao-Jing Wang
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei-Ming Yan
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Dong Xi
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xiao-Ping Luo
- Department of Pediatrics, Tongji Hospital, Wuhan 430030, Hubei Province, China
| | - Xiao-Yang Wan
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Qin Ning
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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24
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Sojoodi M, Erstad DJ, Barrett SC, Salloum S, Zhu S, Qian T, Colon S, Gale EM, Jordan VC, Wang Y, Li S, Ataeinia B, Jalilifiroozinezhad S, Lanuti M, Zukerberg L, Caravan P, Hoshida Y, Chung RT, Bhave G, Lauer GM, Fuchs BC, Tanabe KK. Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver. Cell Mol Gastroenterol Hepatol 2022; 13:1483-1509. [PMID: 35093588 PMCID: PMC9043497 DOI: 10.1016/j.jcmgh.2022.01.015] [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] [Received: 11/05/2021] [Revised: 01/16/2022] [Accepted: 01/19/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix proteins. Extracellular matrix stabilization influences the speed of tissue recovery. Here, we studied the expression and function of peroxidasin (PXDN), a peroxidase that uses hydrogen peroxide to cross-link collagen IV during liver fibrosis progression and regression. METHODS Mouse models of liver fibrosis and cirrhosis patients were analyzed for the expression of PXDN in liver and serum. Pxdn-/- and Pxdn+/+ mice were either treated with carbon tetrachloride for 6 weeks to generate toxin-induced fibrosis or fed with a choline-deficient L-amino acid-defined high-fat diet for 16 weeks to create nonalcoholic fatty liver disease fibrosis. Liver histology, quantitative real-time polymerase chain reaction, collagen content, flowcytometry and immunostaining of immune cells, RNA-sequencing, and liver function tests were analyzed. In vivo imaging of liver reactive oxygen species (ROS) was performed using a redox-active iron complex, Fe-PyC3A. RESULTS In human and mouse cirrhotic tissue, PXDN is expressed by stellate cells and is secreted into fibrotic areas. In patients with nonalcoholic fatty liver disease, serum levels of PXDN increased significantly. In both mouse models of liver fibrosis, PXDN deficiency resulted in elevated monocyte and pro-fibrolysis macrophage recruitment into fibrotic bands and caused decreased accumulation of cross-linked collagens. In Pxdn-/- mice, collagen fibers were loosely organized, an atypical phenotype that is reversible upon macrophage depletion. Elevated ROS in Pxdn-/- livers was observed, which can result in activation of hypoxic signaling cascades and may affect signaling pathways involved in macrophage polarization such as TNF-a via NF-kB. Fibrosis resolution in Pxdn-/- mice was associated with significant decrease in collagen content and improved liver function. CONCLUSION PXDN deficiency is associated with increased ROS levels and a hypoxic liver microenvironment that can regulate recruitment and programming of pro-resolution macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest a novel pathway that is involved in the resolution of scar tissue.
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Affiliation(s)
- Mozhdeh Sojoodi
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Derek J. Erstad
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Stephen C. Barrett
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Shadi Salloum
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Shijia Zhu
- Liver Tumor Translational Research Program, Simmons 22 Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tongqi Qian
- Liver Tumor Translational Research Program, Simmons 22 Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Selene Colon
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Eric M. Gale
- Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Veronica Clavijo Jordan
- Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Yongtao Wang
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Shen Li
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Bahar Ataeinia
- Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Michael Lanuti
- Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Lawrence Zukerberg
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Peter Caravan
- Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons 22 Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Raymond T. Chung
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Gautam Bhave
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Georg M. Lauer
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Bryan C. Fuchs
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kenneth K. Tanabe
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,Correspondence Address correspondence to: Kenneth K. Tanabe, Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. tel: (617) 724-3868.
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25
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Papachristoforou E, Ramachandran P. Macrophages as key regulators of liver health and disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 368:143-212. [PMID: 35636927 DOI: 10.1016/bs.ircmb.2022.04.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Macrophages are a heterogeneous population of innate immune cells and key cellular components of the liver. Hepatic macrophages consist of embryologically-derived resident Kupffer cells (KC), recruited monocyte-derived macrophages (MDM) and capsular macrophages. Both the diversity and plasticity of hepatic macrophage subsets explain their different functions in the maintenance of hepatic homeostasis and in injury processes in acute and chronic liver diseases. In this review, we assess the evidence for macrophage involvement in regulating both liver health and injury responses in liver diseases including acute liver injury (ALI), chronic liver disease (CLD) (including liver fibrosis) and hepatocellular carcinoma (HCC). In healthy livers, KC display critical functions such as phagocytosis, danger signal recognition, cytokine release, antigen processing and the ability to orchestrate immune responses and maintain immunological tolerance. However, in most liver diseases there is a striking hepatic MDM expansion, which orchestrate both disease progression and regression. Single-cell approaches have transformed our understanding of liver macrophage heterogeneity, dynamics, and functions in both human samples and preclinical models. We will further discuss the new insights provided by these approaches and how they are enabling high-fidelity work to specifically identify pathogenic macrophage subpopulations. Given the important role of macrophages in regulating injury responses in a broad range of settings, there is now a huge interest in developing new therapeutic strategies aimed at targeting macrophages. Therefore, we also review the current approaches being used to modulate macrophage function in liver diseases and discuss the therapeutic potential of targeting macrophage subpopulations as a novel treatment strategy for patients with liver disorders.
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Affiliation(s)
- Eleni Papachristoforou
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom
| | - Prakash Ramachandran
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom.
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26
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Hefler J, Marfil-Garza BA, Pawlick RL, Freed DH, Karvellas CJ, Bigam DL, Shapiro AMJ. Preclinical models of acute liver failure: a comprehensive review. PeerJ 2021; 9:e12579. [PMID: 34966588 PMCID: PMC8667744 DOI: 10.7717/peerj.12579] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/10/2021] [Indexed: 12/14/2022] Open
Abstract
Acute liver failure is marked by the rapid deterioration of liver function in a previously well patient over period of days to weeks. Though relatively rare, it is associated with high morbidity and mortality. This makes it a challenging disease to study clinically, necessitating reliance on preclinical models as means to explore pathophysiology and novel therapies. Preclinical models of acute liver failure are artificial by nature, and generally fall into one of three categories: surgical, pharmacologic or immunogenic. This article reviews preclinical models of acute liver failure and considers their relevance in modeling clinical disease.
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Affiliation(s)
- Joshua Hefler
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Braulio A Marfil-Garza
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.,National Institutes of Medical Sciences & Nutrition Salvador Zubiran, Mexico City, Mexico.,CHRISTUS-LatAm Hub Excellence & Innovation Center, Monterrey, Mexico
| | - Rena L Pawlick
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Darren H Freed
- Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Constantine J Karvellas
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.,Department of Critical Care Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - David L Bigam
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - A M James Shapiro
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.,Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
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27
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Zhao D, Yang F, Wang Y, Li S, Li Y, Hou F, Yang W, Liu D, Tao Y, Li Q, Wang J, He F, Tang L. ALK1 signaling is required for the homeostasis of Kupffer cells and prevention of bacterial infection. J Clin Invest 2021; 132:150489. [PMID: 34874921 PMCID: PMC8803331 DOI: 10.1172/jci150489] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 11/30/2021] [Indexed: 11/18/2022] Open
Abstract
Macrophages are highly heterogeneous immune cells that fulfill tissue-specific functions. Tissue-derived signals play a critical role in determining macrophage heterogeneity. However, these signals remain largely unknown. The BMP receptor activin receptor–like kinase 1 (ALK1) is well known for its role in blood vessel formation; however, its role within the immune system has never been revealed to our knowledge. Here, we found that BMP9/BMP10/ALK1 signaling controlled the identity and self-renewal of Kupffer cells (KCs) through a Smad4-dependent pathway. In contrast, ALK1 was dispensable for the maintenance of macrophages located in the lung, kidney, spleen, and brain. Following ALK1 deletion, KCs were lost over time and were replaced by monocyte-derived macrophages. These hepatic macrophages showed significantly reduced expression of the complement receptor VSIG4 and alterations in immune zonation and morphology, which is important for the tissue-specialized function of KCs. Furthermore, we found that this signaling pathway was important for KC-mediated Listeria monocytogenes capture, as the loss of ALK1 and Smad4 led to a failure of bacterial capture and overwhelming disseminated infections. Thus, ALK1 signaling instructs a tissue-specific phenotype that allows KCs to protect the host from systemic bacterial dissemination.
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Affiliation(s)
- Dianyuan Zhao
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Fengjiao Yang
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Yang Wang
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Site Li
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Yang Li
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Fei Hou
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Wenting Yang
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Di Liu
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Yuandong Tao
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Qian Li
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Jing Wang
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuchu He
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Li Tang
- Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
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Ait Ahmed Y, Fu Y, Rodrigues RM, He Y, Guan Y, Guillot A, Ren R, Feng D, Hidalgo J, Ju C, Lafdil F, Gao B. Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners. Cell Mol Immunol 2021; 18:2165-2176. [PMID: 34282300 PMCID: PMC8429713 DOI: 10.1038/s41423-021-00731-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Kupffer cells (KCs), which are liver-resident macrophages, originate from the fetal yolk sac and represent one of the largest macrophage populations in the body. However, the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial. Here, we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy (PHx) and uncover the underlying mechanisms. By using several strains of genetically modified mice and performing immunohistochemical analyses, we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx. Peak KC proliferation was impaired in Il6-knockout (KO) mice and restored after the administration of IL-6 protein, whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice. The source of IL-6 was identified using hepatocyte- and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx. Moreover, peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx, suggesting that IL-6 signaling directly promotes KC proliferation. Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1 (SIRT1) contributed to IL-6-mediated KC proliferation in vitro. Genetic deletion of the Sirt1 gene in myeloid cells, including KCs, impaired KC proliferation after PHx. In conclusion, our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation, which is dependent on IL-6 and SIRT1 activation in KCs.
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Affiliation(s)
- Yeni Ait Ahmed
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Université Paris-Est-Créteil, Créteil, France
| | - Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Robim M Rodrigues
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Adrien Guillot
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Ruixue Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Juan Hidalgo
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Fouad Lafdil
- Université Paris-Est-Créteil, Créteil, France.
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.
- Institut Universitaire de France (IUF), Paris, France.
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
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Vishnyakova P, Poltavets A, Karpulevich E, Maznina A, Vtorushina V, Mikhaleva L, Kananykhina E, Lokhonina A, Kovalchuk S, Makarov A, Elchaninov A, Sukhikh G, Fatkhudinov T. The response of two polar monocyte subsets to inflammation. Biomed Pharmacother 2021; 139:111614. [PMID: 33930675 DOI: 10.1016/j.biopha.2021.111614] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/31/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Macrophages are a central component of innate immunity that play an important role in the defense of the organism. Macrophages are highly plastic and are activated by interaction with other cells and environmental factors. In this work, we study the effect of lipopolysaccharide on macrophages derived from the two most polar (CD14+ and CD16+ monocytes) as well as the intermediate subset of blood monocytes from healthy donors and assess what happens to the subset most prone to polarization on the transcriptomic and proteomic level. It has been shown that, according to primary pro-inflammatory polarization markers, their cytokine profile, and their phagocytic activity, macrophages derived from CD14+ monocytes exhibit higher sensitivity to inducers of pro-inflammatory polarization. Flow cytometry analysis revealed increased levels of CD86, while secretome analysis demonstrated significant increase of pro-inflammatory and anti-inflammatory cytokines observed in CD14+-derived macrophages, as compared to CD16+-derived macrophages in conditioned media. Assessment of the transcriptome and proteome of CD14+-derived macrophages with further bioinformatic analysis identified the most significant differences after polarization towards the pro-inflammatory phenotype. Immune-, membrane-, IFN-γ-, cytokine-, and defense-associated pathways were found significantly prevalent, while downregulated pathways were represented by RNA binding-, housekeeping-, exocytosis-, intracellular transport-, peptide and amide metabolic-related signaling. This data could be useful for macrophage-based cell therapeutics of cancer, as it provides additional background for the manipulation of donor monocytes intended for back transplantation.
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Affiliation(s)
- P Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; Рeoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia.
| | - A Poltavets
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - E Karpulevich
- Ivannikov Institute for System Programming of the Russian Academy of Sciences, 109004 Moscow, Russia; Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | - A Maznina
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | - V Vtorushina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - L Mikhaleva
- Scientific Research Institute of Human Morphology, 117418 Moscow, Russia
| | - E Kananykhina
- Scientific Research Institute of Human Morphology, 117418 Moscow, Russia
| | - A Lokhonina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; Рeoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - S Kovalchuk
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
| | - A Makarov
- Рeoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia; Scientific Research Institute of Human Morphology, 117418 Moscow, Russia
| | - A Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; Scientific Research Institute of Human Morphology, 117418 Moscow, Russia
| | - G Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - T Fatkhudinov
- Рeoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia; Scientific Research Institute of Human Morphology, 117418 Moscow, Russia
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Zwicker C, Bujko A, Scott CL. Hepatic Macrophage Responses in Inflammation, a Function of Plasticity, Heterogeneity or Both? Front Immunol 2021; 12:690813. [PMID: 34177948 PMCID: PMC8220199 DOI: 10.3389/fimmu.2021.690813] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
With the increasing availability and accessibility of single cell technologies, much attention has been given to delineating the specific populations of cells present in any given tissue. In recent years, hepatic macrophage heterogeneity has also begun to be examined using these strategies. While previously any macrophage in the liver was considered to be a Kupffer cell (KC), several studies have recently revealed the presence of distinct subsets of hepatic macrophages, including those distinct from KCs both under homeostatic and non-homeostatic conditions. This heterogeneity has brought the concept of macrophage plasticity into question. Are KCs really as plastic as once thought, being capable of responding efficiently and specifically to any given stimuli? Or are the differential responses observed from hepatic macrophages in distinct settings due to the presence of multiple subsets of these cells? With these questions in mind, here we examine what is currently understood regarding hepatic macrophage heterogeneity in mouse and human and examine the role of heterogeneity vs plasticity in regards to hepatic macrophage responses in settings of both pathogen-induced and sterile inflammation.
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Affiliation(s)
- Christian Zwicker
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Anna Bujko
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Charlotte L. Scott
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
- Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland
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31
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Melo-Silva CR, Alves-Peixoto P, Heath N, Tang L, Montoya B, Knudson CJ, Stotesbury C, Ferez M, Wong E, Sigal LJ. Resistance to lethal ectromelia virus infection requires Type I interferon receptor in natural killer cells and monocytes but not in adaptive immune or parenchymal cells. PLoS Pathog 2021; 17:e1009593. [PMID: 34015056 PMCID: PMC8172060 DOI: 10.1371/journal.ppat.1009593] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 06/02/2021] [Accepted: 04/28/2021] [Indexed: 11/18/2022] Open
Abstract
Type I interferons (IFN-I) are antiviral cytokines that signal through the ubiquitous IFN-I receptor (IFNAR). Following footpad infection with ectromelia virus (ECTV), a mouse-specific pathogen, C57BL/6 (B6) mice survive without disease, while B6 mice broadly deficient in IFNAR succumb rapidly. We now show that for survival to ECTV, only hematopoietic cells require IFNAR expression. Survival to ECTV specifically requires IFNAR in both natural killer (NK) cells and monocytes. However, intrinsic IFNAR signaling is not essential for adaptive immune cell responses or to directly protect non-hematopoietic cells such as hepatocytes, which are principal ECTV targets. Mechanistically, IFNAR-deficient NK cells have reduced cytolytic function, while lack of IFNAR in monocytes dampens IFN-I production and hastens virus dissemination. Thus, during a pathogenic viral infection, IFN-I coordinates innate immunity by stimulating monocytes in a positive feedback loop and by inducing NK cell cytolytic function.
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Affiliation(s)
- Carolina R. Melo-Silva
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Pedro Alves-Peixoto
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Natasha Heath
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Lingjuan Tang
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Brian Montoya
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Cory J. Knudson
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Colby Stotesbury
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Maria Ferez
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Eric Wong
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Luis J. Sigal
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Stegelmeier AA, Darzianiazizi M, Hanada K, Sharif S, Wootton SK, Bridle BW, Karimi K. Type I Interferon-Mediated Regulation of Antiviral Capabilities of Neutrophils. Int J Mol Sci 2021; 22:4726. [PMID: 33946935 PMCID: PMC8125486 DOI: 10.3390/ijms22094726] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/09/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
Interferons (IFNs) are induced by viruses and are the main regulators of the host antiviral response. They balance tissue tolerance and immune resistance against viral challenges. Like all cells in the human body, neutrophils possess the receptors for IFNs and contribute to antiviral host defense. To combat viruses, neutrophils utilize various mechanisms, such as viral sensing, neutrophil extracellular trap formation, and antigen presentation. These mechanisms have also been linked to tissue damage during viral infection and inflammation. In this review, we presented evidence that a complex cross-regulatory talk between IFNs and neutrophils initiates appropriate antiviral immune responses and regulates them to minimize tissue damage. We also explored recent exciting research elucidating the interactions between IFNs, neutrophils, and severe acute respiratory syndrome-coronavirus-2, as an example of neutrophil and IFN cross-regulatory talk. Dissecting the IFN-neutrophil paradigm is needed for well-balanced antiviral therapeutics and development of novel treatments against many major epidemic or pandemic viral infections, including the ongoing pandemic of the coronavirus disease that emerged in 2019.
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Affiliation(s)
| | | | | | | | | | - Byram W. Bridle
- Correspondence: (B.W.B.); (K.K.); Tel.: +1-(519)-824-4120 (ext. 54657) (B.W.B.); +1-(519)-824-4120 (ext. 54668) (K.K.)
| | - Khalil Karimi
- Correspondence: (B.W.B.); (K.K.); Tel.: +1-(519)-824-4120 (ext. 54657) (B.W.B.); +1-(519)-824-4120 (ext. 54668) (K.K.)
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33
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Characterization of the inflammatory microenvironment and hepatic macrophage subsets in experimental hepatocellular carcinoma models. Oncotarget 2021; 12:562-577. [PMID: 33796224 PMCID: PMC7984829 DOI: 10.18632/oncotarget.27906] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. HCC typically develops on a background of chronic inflammation and fibrosis with tumor associated macrophages (TAMs) playing an important role in chronic inflammation-induced HCC and progression. However, the liver harbors unique macrophages, resident liver Kupffer cells (KCs) and monocyte-derived macrophages (Mo-Mφ), and their contribution to HCC and to the population of TAMs is incompletely known. Here, we characterized the tumor microenvironment and the proportion and transcriptional profile of hepatic macrophages (Mφ) in two commonly used HCC mouse models. A gradually increased expression of inflammatory, immune regulatory, fibrotic and cell proliferation pathways and markers was observed during diethylnitrosamine (DEN)- and non-alcoholic steatohepatitis (NASH)-induced HCC development. The transcriptional phenotypes of isolated hepatic Mφ subsets were clearly distinct and shifted during HCC development, with mixed pro-inflammatory and tumor-promoting expression profiles. There were marked differences between the models as well, with Mφ in NASH-HCC exhibiting a more immunomodulatory phenotype, in conjunction with an upregulation of lipid metabolism genes. Our data show that at least some infiltrated macrophages display expression of pro-tumoral markers, and that Kupffer cells are part of the population of TAMs and enhance tumor progression. These insights are useful to further unravel sequential pathogenic events during hepatocarcinogenesis and direct future development of new treatment strategies for HCC.
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Zhou D, Yang F, Lin L, Tang L, Li L, Yang Y, Liu D, Zhang C, Wu T, Wei H, Zhang X, Zhang L. The sirtuin 1 activator SRT1720 alleviated endotoxin-induced fulminant hepatitis in mice. Exp Anim 2021; 70:302-310. [PMID: 33678756 PMCID: PMC8390304 DOI: 10.1538/expanim.20-0014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The metabolic sensor sirtuin 1 (SIRT1) also functions as a checkpoint in inflammation, and SRT1720 is a highly active and selective SIRT1 activator shown to
alleviate inflammatory injury in several recent experimental studies. In the present study, the potential effects and underlying mechanisms of SRT1720 on
lipopolysaccharide (LPS)-induced fulminant hepatitis in D-galactosamine (D-Gal)-sensitized mice were investigated. The results indicated that treatment with
SRT1720 inhibited LPS/D-Gal-induced elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated the histological abnormalities,
suppressed the induction of tumor necrosis factor alpha (TNF-α) and IL-6, mitigated the phosphorylation of c-Jun N-terminal kinase (JNK), downregulated the
activities of caspase 8, caspase 9 and caspase 3, decreased the level of cleaved caspase 3, reduced the TUNEL-positive cells, and improved the survival rate of
the LPS/D-Gal-exposed mice. These data indicated that treatment with the SIRT1 activator SRT1720 alleviated LPS/D-Gal-induced fulminant hepatitis, which might
be attributed to the suppressive effects of SRT1720 on TNF-α production and the subsequent activation of the apoptosis cascade.
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Affiliation(s)
- Dan Zhou
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Feng Yang
- Department of Gynaecology and Obstetrics, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Ling Lin
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Li Tang
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Longjiang Li
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Yongqiang Yang
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Dingrong Liu
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Chong Zhang
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Tong Wu
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Huijie Wei
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Xiaoming Zhang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, 188 Tanhualin Road, Wuhan 430061, P.R. China.,Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, 188 Tanhualin Road, Wuhan 430061, P.R. China
| | - Li Zhang
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
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Zhang LL, Zhang XY, Lu YY, Bi YD, Liu XL, Fang F. The Role of Autophagy in Murine Cytomegalovirus Hepatitis. Viral Immunol 2021; 34:241-255. [PMID: 33566740 DOI: 10.1089/vim.2020.0024] [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] [Indexed: 12/13/2022] Open
Abstract
Autophagy is involved in the pathogenesis of multiple pathogen infection. Previous studies have reported that human cytomegalovirus (CMV) activates autophagy in the early stage of infection and then inhibits autophagy. Little is known about the role of autophagy in murine CMV (MCMV) infection, especially in MCMV-induced hepatitis. The purpose of this study is to investigate the role of autophagy in MCMV hepatitis. BALB/c mice were infected with MCMV and a series of experiments involving western blot, immunofluorescence, immunohistochemistry, H&E (Hematoxylin and Eosin) staining and quantitative real-time polymerase chain reaction were performed in this study. The expression of SQSTM1/p62, PI3K, the ratio of phosphorylated Akt to total Akt, and the ratio of phosphorylated mammalian target of rapamycin (mTOR) to total mTOR were increased, and the expression of light-chain 3 (LC3)-II were decreased in the livers of infected mice on days 3 and 7 postinfection (p.i.). Compared with the untreated infected group, increased transcription level of MCMV glycoprotein B (gB), increased expression levels of interleukin1-β (IL-1β), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), decreased expression level of type I interferon α (IFN-α), as well as aggravated liver pathological injury were detected in starvation-treated infected group on days 3 and 7 p.i.; whereas decreased transcription level of MCMV gB, decreased expression levels of IL-1β, AST and ALT, increased expression level of type I IFN-α, as well as alleviated liver pathological injury were detected in chloroquine (CQ)-treated infected group on day 3 p.i. In conclusion, autophagy is inhibited through activating the PI3K/Akt/mTOR pathway in the liver of BALB/c mice during MCMV infection, and autophagy may promote MCMV replication and aggravate liver pathological damage and inflammation. Further understanding of the interactions between autophagy and MCMV infection and its potential mechanism may bring new important cues to the control of MCMV infection and antiviral therapy.
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Affiliation(s)
- Lin-Lin Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin-Yan Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan-Yuan Lu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Dan Bi
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Lou Liu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Fang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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36
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Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol 2020; 18:45-56. [PMID: 33041338 DOI: 10.1038/s41423-020-00558-8] [Citation(s) in RCA: 410] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.
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Affiliation(s)
- Yankai Wen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Joeri Lambrecht
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.
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Yang Y, Ying G, Wu F, Chen Z. sTim-3 alleviates liver injury via regulation of the immunity microenvironment and autophagy. Cell Death Discov 2020; 6:62. [PMID: 32714569 PMCID: PMC7376253 DOI: 10.1038/s41420-020-00299-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/20/2020] [Accepted: 07/06/2020] [Indexed: 12/13/2022] Open
Abstract
Liver failure (LF) is a monocyte/macrophage-mediated liver injury that has been associated with inflammatory mediators. However, the mechanism through which monocytes/macrophages regulate LF has not been fully elucidated. In this study, we investigated the role of soluble T-cell immunoglobulin domain and mucin domain-containing molecule-3 (sTim-3) in inhibition of release of inflammatory mediators. We further assess this role in protection against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver failure (ALF), via monocyte/macrophage regulation and autophagy induction in mice. Our findings indicate significantly higher plasma sTim-3 in acute-on-chronic liver failure (ACLF) group relative to other groups, with this trend associated with disease progression. Furthermore, infiltrated recombinant sTim-3 inhibited release of various inflammatory mediators, including cytokines and human high-mobility group box-1 (HMGB1), potentially via autophagy induction. Furthermore, H&E staining and the low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ALF mice, supported that recombinant sTim-3 effectively alleviated liver injury. Moreover, sTim-3 induced changes in monocyte/macrophage population in mice's liver or blood, which consequently caused a reduction in proinflammatory CD11bhiF4/80lo monocyte-derived macrophages and Ly-6C(+)CD11b(+) monocytes. Conversely, sTim-3 increased autophagy levels of hepatic CD11b(+) monocyte-derived macrophages and decreased apoptosis rate of CD11b (+) monocytes in the blood. Collectively, our findings demonstrated that sTim-3 alleviated inflammatory response and liver injury by promoting autophagy and regulating monocyte/macrophage function. This indicates its potential for future development of novel therapeutic strategies against LF.
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Affiliation(s)
- Ying Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Gaoxiang Ying
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
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Van Campenhout S, Tilleman L, Lefere S, Vandierendonck A, Raevens S, Verhelst X, Geerts A, Van Nieuwerburgh F, Van Vlierberghe H, Devisscher L. Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model. Metabolism 2020; 107:154220. [PMID: 32243868 DOI: 10.1016/j.metabol.2020.154220] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/19/2020] [Accepted: 03/30/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Obesity, diabetes and associated non-alcoholic steatohepatitis (NASH) are rising risk factors for hepatocellular carcinoma (HCC). Macrophages are important immune cells involved in inflammation and tumour development. Macrophage inositol-requiring enzyme 1 alpha (IRE1α), an ER-stress protein, has been shown to be involved in macrophage cytokine production, and myeloid-specific IRE1α knock-out (myeloid IRE1α-KO) mice showed reduced weight gain during high-fat diet feeding. However, the effect of myeloid IRE1α on NASH and subsequent HCC development has not been examined. Here, we characterized the transcriptional profile of the hepatic macrophage population in a diabetes-NASH-HCC mouse model, and investigated the effect of myeloid-specific IRE1α deletion on the phenotype of hepatic macrophage subsets and experimental NASH-HCC development. METHODS Mice with non-functional myeloid IRE1α were created by crossing Ire1a floxed mice with Lysm-Cre mice. Two-day old myeloid IRE1α-KO and wild type (WT) mice were subcutaneously injected with streptozotocin (STZ), and male mice were fed a high-fat, -sucrose, -cholesterol diet (Western diet, WD) from the age of 4 weeks until 21 weeks. Control myeloid IRE1α-KO and WT mice received a PBS injection and were fed a matched control diet. These mice were evaluated for obesity, diabetes, NASH and HCC. The hepatic macrophage population was evaluated by flow cytometry and RNA sequencing on FACS-isolated macrophage subsets. RESULTS STZ-injection and WD feeding resulted in an impaired glucose tolerance, advanced NASH with fibrosis, and HCC development. Myeloid IRE1α-KO STZ mice showed lower fasting glucose levels at the start of WD feeding, and an improved glucose tolerance and attenuated HCC development after 17 weeks of WD feeding despite a similar degree of liver steatosis and inflammation compared to WT mice. Transcriptomic analysis of WT liver Kupffer cells, macrophages and monocytes revealed phenotypical changes in those cell subsets during NASH-HCC development. Isolated liver Kupffer cells and macrophages from mice with a myeloid IRE1α deletion showed downregulated pathways involved in immune system activation and metabolic pathways (only in Kupffer cells), whereas pathways involved in cell division and metabolism were upregulated in monocytes. These transcriptional differences were attenuated during NASH-HCC development. CONCLUSION Our results show that myeloid-specific IRE1α deletion results in an altered transcriptional profile of hepatic macrophages and dampens diabetes-induced NASH-HCC development, possibly by attenuated diabetes induction.
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Affiliation(s)
- Sanne Van Campenhout
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium; Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 3, 9000 Ghent, Belgium.
| | - Laurentijn Tilleman
- Lab of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium.
| | - Astrid Vandierendonck
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium.
| | - Sarah Raevens
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium.
| | - Xavier Verhelst
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium.
| | - Anja Geerts
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium.
| | - Filip Van Nieuwerburgh
- Lab of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 2, 9000 Ghent, Belgium.
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Entrance 36 - Floor 3, 9000 Ghent, Belgium.
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Gawish R, Bulat T, Biaggio M, Lassnig C, Bago-Horvath Z, Macho-Maschler S, Poelzl A, Simonović N, Prchal-Murphy M, Rom R, Amenitsch L, Ferrarese L, Kornhoff J, Lederer T, Svinka J, Eferl R, Bosmann M, Kalinke U, Stoiber D, Sexl V, Krmpotić A, Jonjić S, Müller M, Strobl B. Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1. Cell Rep 2020; 26:2394-2406.e5. [PMID: 30811989 DOI: 10.1016/j.celrep.2019.02.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 12/13/2018] [Accepted: 02/05/2019] [Indexed: 12/11/2022] Open
Abstract
Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen.
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Affiliation(s)
- Riem Gawish
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Tanja Bulat
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Mario Biaggio
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Caroline Lassnig
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Biomodels Austria, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | | | - Sabine Macho-Maschler
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Biomodels Austria, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Andrea Poelzl
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Natalija Simonović
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Michaela Prchal-Murphy
- Institute of Pharmacology and Toxicology, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Rita Rom
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Lena Amenitsch
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Luca Ferrarese
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Juliana Kornhoff
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Therese Lederer
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Jasmin Svinka
- Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Robert Eferl
- Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Markus Bosmann
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
| | - Dagmar Stoiber
- Ludwig Boltzmann Institute for Cancer Research, Vienna and Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
| | - Veronika Sexl
- Institute of Pharmacology and Toxicology, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Astrid Krmpotić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Stipan Jonjić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Biomodels Austria, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
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Selective reconstitution of IFN‑γ gene function in Ncr1+ NK cells is sufficient to control systemic vaccinia virus infection. PLoS Pathog 2020; 16:e1008279. [PMID: 32023327 PMCID: PMC7028289 DOI: 10.1371/journal.ppat.1008279] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 02/18/2020] [Accepted: 12/11/2019] [Indexed: 12/22/2022] Open
Abstract
IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course and outcome of infectious diseases, autoimmunity, and cancer. To selectively analyze the function of innate immune cell-derived IFN-γ, we generated conditional IFN-γOFF mice, in which endogenous IFN-γ expression is disrupted by a loxP flanked gene trap cassette inserted into the first intron of the IFN-γ gene. IFN-γOFF mice were intercrossed with Ncr1-Cre or CD4-Cre mice that express Cre mainly in NK cells (IFN-γNcr1-ON mice) or T cells (IFN-γCD4-ON mice), respectively. Rosa26RFP reporter mice intercrossed with Ncr1-Cre mice showed selective RFP expression in more than 80% of the NK cells, while upon intercrossing with CD4-Cre mice abundant RFP expression was detected in T cells, but also to a minor extent in other immune cell subsets. Previous studies showed that IFN-γ expression is needed to promote survival of vaccinia virus (VACV) infection. Interestingly, during VACV infection of wild type and IFN-γCD4-ON mice two waves of serum IFN-γ were induced that peaked on day 1 and day 3/4 after infection. Similarly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses, of which the first one was moderately and the second one profoundly reduced when compared with WT mice. Furthermore, IFN-γNcr1-ON as well as IFN-γCD4-ON mice survived VACV infection, whereas IFN-γOFF mice did not. As expected, ex vivo analysis of splenocytes derived from VACV infected IFN-γNcr1-ON mice showed IFN-γ expression in NK cells, but not T cells, whereas IFN-γOFF mice showed IFN-γ expression neither in NK cells nor T cells. VACV infected IFN-γNcr1-ON mice mounted normal cytokine responses, restored neutrophil accumulation, and showed normal myeloid cell distribution in blood and spleen. Additionally, in these mice normal MHC-II expression was detected on peripheral macrophages, whereas IFN-γOFF mice did not show MHC-II expression on such cells. In conclusion, upon VACV infection Ncr1 positive cells including NK cells mount two waves of early IFN-γ responses that are sufficient to promote the induction of protective anti-viral immunity. Viral infections induce interferon (IFN) responses that constitute a first line of defense. Type II IFN (IFN-γ) is required for protection against lethal vaccinia virus (VACV) infection. To address the cellular origin of protective IFN-γ responses during VACV infection, we generated IFN-γOFF mice, in which the endogenous IFN-γ gene function can be reconstituted in a Cre-dependent manner. IFN-γOFF mice were intercrossed with Ncr1-Cre mice that express Cre selectively in Ncr1+ innate cell subsests such as NK cells. Surprisingly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses. Reconstitution of innate IFN-γ was sufficient to restore cytokine responses that supported normal myeloid cell distribution and survival upon VACV infection. In conclusion, IFN-γ derived from Ncr1+ innate immune cells is sufficient to elicit fully effective immune responses upon VACV infection. Our new mouse model is suitable to further address the role of Ncr1+ cell-derived IFN-γ also in other models of infection, as well as of autoimmunity and cancer.
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van der Heide D, Weiskirchen R, Bansal R. Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases. Front Immunol 2019; 10:2852. [PMID: 31849997 PMCID: PMC6901832 DOI: 10.3389/fimmu.2019.02852] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/20/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.
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Affiliation(s)
- Daphne van der Heide
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, Netherlands
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, Netherlands
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Unveiling the depletion of Kupffer cells in experimental hepatocarcinogenesis through liver macrophage subtype-specific markers. J Hepatol 2019; 71:631-633. [PMID: 31213365 DOI: 10.1016/j.jhep.2019.03.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/10/2019] [Indexed: 01/09/2023]
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Borst K, Graalmann T, Kalinke U. Reply to: "Unveiling the depletion of Kupffer cells in experimental hepatocarcinogenesis through liver macrophage subtype-specific markers". J Hepatol 2019; 71:633-635. [PMID: 31227257 DOI: 10.1016/j.jhep.2019.05.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/18/2019] [Accepted: 05/22/2019] [Indexed: 12/04/2022]
Affiliation(s)
- Katharina Borst
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Germany
| | - Theresa Graalmann
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Brunswick, Germany; Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Brunswick, Germany; Cluster of Excellence - Resolving Infection Susceptibility (RESIST), Hannover Medical School, Hannover, Germany.
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Borst K, Graalmann T, Kalinke U. Reply to: "Lack of Kupffer cell depletion in diethylnitrosamine-induced hepatic inflammation". J Hepatol 2019; 70:815-816. [PMID: 30712975 DOI: 10.1016/j.jhep.2018.12.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 12/31/2018] [Indexed: 01/30/2023]
Affiliation(s)
- Katharina Borst
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Germany
| | - Theresa Graalmann
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hanover Medical School and the Helmholtz Centre for Infection Research, RESIST, Cluster of Excellence 2155, Hanover Medical School, Carl-Neuberg-Straße 1, 30625 Hanover, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hanover Medical School and the Helmholtz Centre for Infection Research, RESIST, Cluster of Excellence 2155, Hanover Medical School, Carl-Neuberg-Straße 1, 30625 Hanover, Germany.
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Tsay HC, Yuan Q, Balakrishnan A, Kaiser M, Möbus S, Kozdrowska E, Farid M, Tegtmeyer PK, Borst K, Vondran FWR, Kalinke U, Kispert A, Manns MP, Ott M, Sharma AD. Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis. J Hepatol 2019; 70:722-734. [PMID: 30582979 DOI: 10.1016/j.jhep.2018.12.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 12/02/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive. METHODS Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. RESULTS Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis. CONCLUSIONS Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis. LAY SUMMARY Liver fibrosis majorly contributes to mortality resulting from various liver diseases. We discovered a small RNA known as miRNA-221-3p, whose downregulation in hepatocytes results in reduced liver fibrosis. Thus, inhibition of miRNA-221-3p may serve as one of the therapeutic approaches for treatment of liver fibrosis.
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Affiliation(s)
- Hsin-Chieh Tsay
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Qinggong Yuan
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Marina Kaiser
- Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
| | - Selina Möbus
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Emilia Kozdrowska
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marwa Farid
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Human Cytogenetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
| | - Pia-Katharina Tegtmeyer
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Katharina Borst
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Regenerative Medicine and Experimental Surgery (RedMediES), Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Ulrich Kalinke
- TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Andreas Kispert
- Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Ott
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
| | - Amar Deep Sharma
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
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Kessler SM, Hoppstädter J, Hosseini K, Laggai S, Haybaeck J, Kiemer AK. Lack of Kupffer cell depletion in diethylnitrosamine-induced hepatic inflammation. J Hepatol 2019; 70:813-815. [PMID: 30686611 DOI: 10.1016/j.jhep.2018.11.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 11/21/2018] [Accepted: 11/23/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Sonja M Kessler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Jessica Hoppstädter
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Kevan Hosseini
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Stephan Laggai
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Johannes Haybaeck
- Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria; Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Alexandra K Kiemer
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
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Wanve M, Kaur H, Sarmah D, Saraf J, Pravalika K, Vats K, Kalia K, Borah A, Yavagal DR, Dave KR, Bhattacharya P. Therapeutic spectrum of interferon-β in ischemic stroke. J Neurosci Res 2018; 97:116-127. [PMID: 30320448 PMCID: PMC7167007 DOI: 10.1002/jnr.24333] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/05/2018] [Accepted: 09/05/2018] [Indexed: 12/16/2022]
Abstract
Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US-FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon-beta (IFN-β), an endogenous cytokine and a key anti-inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN-β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN-β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN-β therapy that may be helpful in improving stroke outcome are also discussed.
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Affiliation(s)
- Madhuri Wanve
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Harpreet Kaur
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Deepaneeta Sarmah
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Jackson Saraf
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Kanta Pravalika
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Kanchan Vats
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Kiran Kalia
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and BioinformaticsAssam UniversitySilcharIndia
| | - Dileep R. Yavagal
- Department of Neurology and NeurosurgeryUniversity of Miami Miller School of MedicineMiamiFlorida
| | - Kunjan R. Dave
- Department of Neurology and NeurosurgeryUniversity of Miami Miller School of MedicineMiamiFlorida
| | - Pallab Bhattacharya
- Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)GandhinagarIndia
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48
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Interfering with Kupffer cell replenishment: New insights into liver injury. J Hepatol 2018; 68:635-637. [PMID: 29463431 DOI: 10.1016/j.jhep.2018.01.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 01/15/2018] [Indexed: 01/30/2023]
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