The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse

Abstract

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.

The immunological characteristics of TSPAN1 expressing B cells in autoimmune hepatitis

“…CXCR3 and CXCR4 were previously reported to be expressed by non-B lymphocyte immune cells and related to retention in the liver ( 26 ). Recent studies showed that CXCR3 and CXCR4 can also be expressed on B cells ( 27 , 28 ). Our study demonstrated that CXCR3 was highly expressed on TSPAN1 + B cells.…”

Antidepressants cheer up hepatic B1 B cells: Hope for the treatment of autoimmune liver diseases?

“…In summary, Almishri and colleagues ( 44 ) have shown that treatment of mice with mirtazapine leads to shifting towards B1 B cells in the liver. It is conceivable that this might elevate hepatic nIgM titers exerting positive effects on liver immune homeostasis.…”

“…The atypical antidepressant, mirtazapine, shows antagonistic effects on several receptors including histamine receptor H1 ( 42 ) and serotonin receptors 5HT3 and 5HT3A ( 43 ) expressed by B cells. Almishri and colleagues ( 44 ) reported that mice treated with mirtazapine showed a drastic reduction of overall B cell numbers in the liver. In particular, remaining liver-localized B cells were skewed towards B1 B cells.…”

“…Almishri et al. ( 44 ) observed that hepatic B cells of mice treated with mirtazapine show altered cytokine secretion profiles compared to hepatic B cells isolated from control mice. The authors stimulated the isolated hepatic B cells with PMA/ionomycin ( 51 ) to determine which cytokines the cells were primed to secrete.…”

“…FIGURE 1Possible effects of mirtazapine on liver-localized B cells. Almishri and colleagues(44) have demonstrated that treatment of mice with the atypical antidepressant, mirtazapine, leads to an increased proportion of hepatic B1 compared to B2 B cells, suppression of pro-inflammatory cytokine production by B cells and emigration of hepatic B2 B cells from the liver. Figure was created by using biorender.com.…”