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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    • "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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    ABSTRACT: Mounting of the acute inflammatory response is crucial for host defense and pivotal to the development of chronic inflammation, fibrosis, or abscess formation versus the protective response and the need of the host tissues to return to homeostasis. Within self-limited acute inflammatory exudates, novel families of lipid mediators are identified, named resolvins (Rv), protectins, and maresins, which actively stimulate cardinal signs of resolution, namely, cessation of leukocytic infiltration, counterregulation of proinflammatory mediators, and the uptake of apoptotic neutrophils and cellular debris. The biosynthesis of these resolution-phase mediators in sensu stricto is initiated during lipid-mediator class switching, in which the classic initiators of acute inflammation, prostaglandins and leukotrienes (LTs), switch to produce specialized proresolving mediators (SPMs). In this work, we review recent evidence on the structure and functional roles of these novel lipid mediators of resolution. Together, these show that leukocyte trafficking and temporal spatial signals govern the resolution of self-limited inflammation and stimulate homeostasis.
    Cold Spring Harbor perspectives in biology 10/2014; 7(2). DOI:10.1101/cshperspect.a016311 · 8.68 Impact Factor
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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.
    Journal of Neuroinflammation 04/2014; 11(1):72. DOI:10.1186/1742-2094-11-72 · 5.41 Impact Factor
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    • "RvDs and RvE1 were found to significantly contribute to bacterial clearance [33,51]. In addition, resolvins were shown to promote injury repair via increased phosphoinositide 3 kinase-dependent migration and decreased accumulation of apoptotic cells [45,84]. This suggests that resolvin rapidly and ultimately help successful completion of rescue of injuries, rather than lead to incomplete defense. "
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