Resolvin D1 prevents TNF- -mediated disruption of salivary epithelial formation

Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, New York 14214-3092, USA. .
AJP Cell Physiology (Impact Factor: 3.78). 01/2012; 302(9):C1331-45. DOI: 10.1152/ajpcell.00207.2011
Source: PubMed


Sjögren's syndrome is a chronic autoimmune disorder characterized by inflammation of salivary glands resulting in impaired secretory function. Our present studies indicate that chronic exposure of salivary epithelium to TNF-α and/or IFN-γ alters tight junction integrity, leading to secretory dysfunction. Resolvins of the D-series (RvDs) are endogenous lipid mediators derived from DHA that regulate excessive inflammatory responses leading to resolution and tissue homeostasis. In this study, we addressed the hypothesis that activation of the RvD1 receptor ALX/FPR2 in salivary epithelium prevents and/or resolves the TNF-α-mediated disruption of acinar organization and enhances monolayer formation. Our results indicate that 1) the RvD1 receptor ALX/FPR2 is present in fresh, isolated cells from mouse salivary glands and in cell lines of salivary origin; and 2) the agonist RvD1 (100 ng/ml) abolished tight junction and cytoskeletal disruption caused by TNF-α and enhanced cell migration and polarity in salivary epithelium. These effects were blocked by the ALX/FPR2 antagonist butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe. The ALX/FPR2 receptor signals via modulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways since, in our study, blocking PI3K activation with LY294002, a potent and selective PI3K inhibitor, prevented RvD1-induced cell migration. Furthermore, Akt gene silencing with the corresponding siRNA almost completely blocked the ability of Par-C10 cells to migrate. Our findings suggest that RvD1 receptor activation promotes resolution of inflammation and tissue repair in salivary epithelium, which may have relevance in the restoration of salivary gland dysfunction associated with Sjögren's syndrome.

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Available from: Olga Baker, Mar 17, 2014
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    • "Indeed, several in vitro studies performed on microglia show that several LC n-3 PUFA pro-resolving derivatives have potent effects. As an example, RvD1 triggers anti-inflammatory activities and potentiates IL- 4-induced expression of M2 markers in microglial cells and the signaling pathways involved in these processes, in particular the PPARγ signalling pathways (Li et al., 2014;Odusanwo et al., 2012;Wang et al., 2014). In addition, RvD1 inhibits the activation of several proinflammatory signalling pathways, including NFkB and MAPK in microglia cells which express RvD1 receptors ALX (Xu et al., 2013). "

    Full-text · Article · Jan 2016
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    • "RvD1 (100 ng/mL) rescues TNFa-induced tight junction and cytoskeletal disruption , and enhances cell migration and polarity in an ALX-dependent manner. Hence, RvD1 promotes tissue repair in salivary epithelium and restores salivary gland dysfunction associated with Sjögren's syndrome (Odusanwo et al. 2012). In rabbit arterial angioplasty, endogenous biosynthesis of proresolving lipid mediators, including RvD5 and LXB 4 , was identified in the artery wall. "
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    • "Moreover, in murine physiology, we did not identify the murine orthologs of human GPR32, while mouse ALX has been confirmed to express in neuron, astrocyte, microglia, neutrophils, macrophage and monocyte, as well as BV-2 cells [21,30]. Boc-2 is an ALX/FPR2 antagonist, and can block the ability of RvD1 [31]. Thus, we investigated the receptor dependency of RvD1 in microglia M2 polarization by using Boc-2. "
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    ABSTRACT: Microglia play key roles in innate immunity, homeostasis, and neurotropic support in the central nervous system. Similar to macrophages, microglia adopt two different activation phenotypes, the classical and alternative activation. Resolvin D1 (RvD1) is considered to display potent anti-inflammatory and pro-resolving actions in inflammatory models. In this present study, we investigate the effect of RvD1 on IL-4-induced alternative activation in murine BV-2 microglial cells. BV-2 cells were incubated with RvD1 alone, IL-4 alone, or the combination of RvD1 and IL-4. Western blot and immunofluorescence were performed to detect protein levels of alternative activation markers arginase 1 (Arg1), chitinase 3-like 3 (Ym1). Moreover, we investigated the effects of RvD1 on IL-4-induced activation of signal transducer and activators of transcription 6 (STAT6) and peroxisome proliferator-activated receptor gamma (PPARgamma). RvD1 promoted IL-4-induced microglia alternative activation by increasing the expression of Arg1 and Ym1. RvD1 also enhanced phosphorylation of STAT6, nuclear translocation of PPARgamma and the DNA binding activity of STAT6 and PPARgamma. These effects were reversed by butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (a formyl peptide receptor 2 antagonist). Further, the effects of RvD1 and IL-4 on Arg1 and Ym1 were blocked by the application of leflunomide (a STAT6 inhibitor) or GW9662 (a PPARgamma antagonist). Our studies demonstrate that RvD1 promotes IL-4-induced alternative activation via STAT6 and PPARgamma signaling pathways in microglia. These findings suggest that RvD1 may have therapeutic potential for neuroinflammatory diseases.
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