Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation
Odusanwo, Olutayo Adepeju
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Inappropriate or excessive acute inflammation can contribute to chronic diseases. In health, the resolution of inflammation is an active process that terminates inflammatory responses. The recent identification of endogenous lipid-derived mediators of resolution has provided a window to explore the pathobiology of chronic inflammatory disease. Sjögren's Syndrome (SS) is a chronic autoimmune disorder characterized by inflammation of salivary glands resulting in impaired secretory function. SS pathophysiology includes elevated levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18) and interleukin-12 (IL-12). Therefore, controlling the inflammatory response is an important aspect to preserving and maintaining the integrity of the salivary gland. Recent studies indicate that chronic exposure of salivary epithelium to TNF-α and/or IFN-γ alters tight junction (TJ) 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. RvD1 and its biologically more stable aspirin-triggered epimer (AT-RvD1) are RvD subtypes initially identified as being generated during the resolution phase of peritonitis in mice. These molecules limit neutrophil influx; chemokine and pro-inflammatory cytokine production in the inflammatory exudates of mouse peritoneum. In this study, we addressed the hypothesis that activation of the RvD1 receptor FPR2/ALX in salivary epithelium prevents and/or resolves the TNF-α-mediated disruption of acinar organization and enhances monolayer formation. Our results indicate the RvD1 receptor FPR2/ALX is present in fresh isolated cells from mouse salivary glands and in cell lines of salivary origin; the agonist RvD1 (100 ng/ml) abolished TJ and cytoskeletal disruption caused by TNF-ƒÑ and enhanced cell migration and polarity in salivary epithelium. These effects are mediated via modulation of the PI3 kinase/Akt/mTORC2 signaling pathways. 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 SS.