Browsing by Author "Almishri, Wagdi"

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    Recruitment of α4β7 monocytes and neutrophils to the brain in experimental colitis is associated with elevated cytokines and anxiety-like behavior
    (2022-04-04) Cluny, Nina L.; Nyuyki, Kewir D.; Almishri, Wagdi; Griffin, Lateece; Lee, Benjamin H.; Hirota, Simon A.; Pittman, Quentin J.; Swain, Mark G.; Sharkey, Keith A.
    Abstract Background Behavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte–cerebral endothelial cell interactions occur in the brain in experimental colitis, mediated by α4β7 integrin, to initiate neuroimmune activation and anxiety-like behavior. Methods Female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte–cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4β7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist. Results The proportion of classical monocytes expressing α4β7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4β7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils was significantly reduced in mice with colitis. Interleukin-1β and CCL2 levels were elevated in the brain and treatment with anti-α4β7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist. Conclusions In experimental colitis, α4β7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1β mediates anxiety-like behavior.
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    Regulatory Immune-Responses Occurring within the Liver Downstream of Hepatic iNKTcell activation
    (2015-07-07) Almishri, Wagdi; Swain, Mark
    Despite its` high prevalence, the pathogenesis of immune-mediated liver injury is poorly understood. Invariant Natural killer T (iNKT) cells are a distinct innate immune T cell believed to orchestrate a balance between pro-and-anti-inflammatory responses within the liver during immune mediated liver injury. However, the regulatory roles of iNKT cells in the modulation of the hepatic immune response are still poorly defined. In this work we utilized the alpha-galactosylceramide-induced hepatitis model, a model of specific iNKT cell activation, to help us dissect basic immune regulatory mechanisms occurring in the liver during hepatic innate immune activation. We have now documented the rapid recruitment and activation of innate-like regulatory B cells in the liver subsequent to iNKT cell activation. These regulatory B cells were recruited from the spleen and peritoneum. Moreover, depletion of B cells exacerbated iNKT cell-driven liver injury, in association with a profound alteration in the hepatic cytokine milieu and enhanced neutrophil recruitment. This suppression of hepatic inflammation was IL-10 and TGFβ1 independent, and involved activity of ecto-5'-nucleotidase/CD73. IL-22 is an innate cytokine which has been broadly implicated in the regulation of hepatic immunity, and IL-22BP is a secreted specific IL-22 antagonist. In our second paper, we found that activation of hepatic iNKT cells led to the striking, parallel early recruitment of both IL-22 and IL-22BP producing immune cells. Additionally, we found a marked increase in the hepatic expression of both IL-22BP and IL-22R1 in liver biopsies obtained from patients with viral and autoimmune liver diseases compared to normal livers. We also found that the inflammasome plays an important role in regulating IL-22BP expression within liver recruited immune cells and hepatocytes. In this dissertation we have uncovered previously unrecognized regulatory mechanisms induced by activated iNKT cells within the liver. These findings give insight into pathological changes occurring in various human liver diseases in which iNKT cells have been implicated, and in which liver injury is immune-mediated. These findings could potentially be used to develop new regulatory B-cell-based and/or cytokine-based therapies to beneficially alter hepatic innate immune responses in patients suffering with immune-mediated liver diseases.