Abstract
Exposure to trichloroethene (TCE), an occupational and ubiquitous environmental contaminant, is associated with the development of several autoimmune diseases, including autoimmune hepatitis (AIH). However, mechanisms contributing to TCE-mediated AIH are not known. Earlier, we have shown that dichloroacetyl chloride (DCAC), one of the reactive metabolites of TCE with strong acylating capability, can elicit an autoimmune response at much lower dose than TCE in female MRL+/+ mice. Furthermore, Kupffer cells (KCs), the liver resident macrophages, are crucial for hepatic homeostasis, but can also participate in the immunopathogenesis of AIH. However, contribution of KCs in TCE-mediated AIH and the underlying mechanisms are not understood. We hypothesized that increased apoptosis and delayed clearance of apoptotic bodies, due to compromised KC function, will result in the breakdown of self-tolerance, autoimmunity, and ultimately AIH. Therefore, using an in vitro model of immortalized mouse KCs, we investigated the contribution of DCAC in TCE-mediated AIH. KCs were treated with different concentrations of DCAC and apoptosis was measured by Annexin V and PI staining. Also, the impact of DCAC on phagocytic potential of KCs was evaluated. Furthermore, markers of inflammasome (NLRP3 and caspase1) were analyzed by real-time PCR and Western blot analysis. DCAC treatment resulted in significantly increased early and late-stage apoptosis, accompanied with inflammasome activation (NLRP3 increases). DCAC treatment resulted in decreased phagocytic function of KCs in a dose-dependent manner, with reduced MFG-E8 levels (phagocytotic function). Furthermore, DCAC exposure led to induction of phos-ERK and phos-AKT signaling. These findings suggest that DCAC induces apoptosis and inflammasome activation, while compromising the phagocytic function of KCs. Our data support that increased apoptosis and impaired KC function by DCAC could be contributory to TCE-mediated AIH.
Highlights
Trichloroethene is a chlorinated toxic solvent and widely used as industrial degreaser
To evaluate the contribution of dichloroacetyl chloride (DCAC) in TCE-mediated autoimmunity, we investigated the effect of DCAC exposure on cell apoptosis in vitro
One of the major roles of Kupffer cells (KCs) is to clear the apoptotic bodies from the injured liver, and delayed clearance due to compromised phagocytic function of KCs could lead to activation of hepatic inflammatory responses, eventually eliciting an autoimmune response [23]
Summary
Trichloroethene (trichloroethylene, TCE) is a chlorinated toxic solvent and widely used as industrial degreaser. Exposure to TCE is associated with several autoimmune diseases, including autoimmune hepatitis (AIH) [1,2,3]. Compromised phagocytic function of KCs may cause the accumulation of apoptotic cells/bodies, generation of neoantigens, leading to initiation of inflammatory responses in the liver and subsequently AIH [10]. The dysregulation of immune response in AIH is initiated by presentation of self-antigens to naïve T cells by antigen presentation cells, like dendritic cells (DCs) and KCs [11, 12]. Our previous study has shown that long-term TCE exposure (24 or 36 weeks) results in decreased number and function of KCs in the livers of female MRL+/+ mice [2], suggesting that KC function is critical in the pathogenesis of TCE-mediated AIH. Contribution of DCAC in TCEmediated KC dysfunction, cytotoxicity and/or AIH and underlying mechanisms are largely unknown
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