The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse
IntroductionB cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mi...
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.622537/full |
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| author | Wagdi Almishri Wagdi Almishri Wagdi Almishri Rachelle P. Davis Rachelle P. Davis Abdel-Aziz Shaheen Mohammed O. Altonsy Mohammed O. Altonsy Mohammed O. Altonsy Craig N. Jenne Craig N. Jenne Mark G. Swain Mark G. Swain Mark G. Swain |
| author_facet | Wagdi Almishri Wagdi Almishri Wagdi Almishri Rachelle P. Davis Rachelle P. Davis Abdel-Aziz Shaheen Mohammed O. Altonsy Mohammed O. Altonsy Mohammed O. Altonsy Craig N. Jenne Craig N. Jenne Mark G. Swain Mark G. Swain Mark G. Swain |
| author_sort | Wagdi Almishri |
| collection | DOAJ |
| description | IntroductionB cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro.ConclusionMirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology. |
| first_indexed | 2024-12-19T12:05:52Z |
| format | Article |
| id | doaj.art-7c2cfff06b0d4cb4a31244b56b0e20a7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T12:05:52Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7c2cfff06b0d4cb4a31244b56b0e20a72022-12-21T20:22:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.622537622537The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the MouseWagdi Almishri0Wagdi Almishri1Wagdi Almishri2Rachelle P. Davis3Rachelle P. Davis4Abdel-Aziz Shaheen5Mohammed O. Altonsy6Mohammed O. Altonsy7Mohammed O. Altonsy8Craig N. Jenne9Craig N. Jenne10Mark G. Swain11Mark G. Swain12Mark G. Swain13Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, CanadaSnyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaDepartment of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, University of Tripoli, Tripoli, LibyaDepartment of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, CanadaSnyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaDivision of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, CanadaDepartment of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, CanadaSnyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaDepartment of Zoology, Faculty of Science, Sohag University, Sohag, EgyptDepartment of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, CanadaSnyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaDepartment of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, CanadaSnyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaDivision of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, CanadaIntroductionB cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro.ConclusionMirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology.https://www.frontiersin.org/articles/10.3389/fimmu.2021.622537/fullliver diseaseimmunityB cellsinflammationintravital microscopy |
| spellingShingle | Wagdi Almishri Wagdi Almishri Wagdi Almishri Rachelle P. Davis Rachelle P. Davis Abdel-Aziz Shaheen Mohammed O. Altonsy Mohammed O. Altonsy Mohammed O. Altonsy Craig N. Jenne Craig N. Jenne Mark G. Swain Mark G. Swain Mark G. Swain The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse Frontiers in Immunology liver disease immunity B cells inflammation intravital microscopy |
| title | The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse |
| title_full | The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse |
| title_fullStr | The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse |
| title_full_unstemmed | The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse |
| title_short | The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse |
| title_sort | antidepressant mirtazapine rapidly shifts hepatic b cell populations and functional cytokine signatures in the mouse |
| topic | liver disease immunity B cells inflammation intravital microscopy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.622537/full |
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