A Targeted Approach to Managing Salivary Gland Inflammation Using Resolvins

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ABSTRACT Sjögren's syndrome (SS) is an autoimmune disease characterized by chronic inflammation and diminished secretory function of the salivary glands (SG). Diagnostic features include dry mouth, lymphocytic infiltration into the SG and presence of antinuclear autoantibodies in plasma. SS greatly decreases the patient’s quality of life, and although extensive investigation has been done to understand it, causes of and effective treatments for the disease are still unknown. In light of the high degree of need and the limitations of current therapies, development of novel treatments to decrease inflammation and restore SG secretory function is essential. Our previous studies demonstrated that SG express the AT-RvD1 receptor ALX/FPR2 to block pro-inflammatory cytokine signaling, thereby promoting cell survival and tissue integrity in SS. More recently, we demonstrated that AT-RvD1 treatment in SS-like NOD/ShiLtJ mice fully preserves secretory functioning, downregulates pro- inflammatory cytokine expression and promotes pro-resolving signaling pathways. Encouraging as these results may be, however, lymphocytic infiltration persists in AT-RvD1 treated SS mice, raising the possibility of future pro-inflammatory cytokine production and possible recurrence of hypofunction. Moreover, we face issues related to the properties of resolvins themselves that must be overcome for clinical applications to be achieved. Specifically, a significant portion of administered resolvins (RvD1 included) do not reach their intended destination with the desired regularity because they are quickly inactivated by eicosanoid oxidoreductases (EOR) and their effects can be diffusely distributed throughout the body. Furthermore, the problem of instability extends to the AT forms, which are somewhat less susceptible to inactivation. In addition to these issues of durability, resolvins are relatively expensive, and when taken together, these concerns raise questions about the feasibility of any treatment requiring large doses to be introduced into the blood stream. In response, we believe that all of these issues may be addressed by infusing AT-RvD1 retrograde to the salivary ducts, which could allow the benefits demonstrated by AT-RvD1 (i.e., preserved and/or restored saliva secretion) to be retained while addressing areas of weakness discussed earlier. Moreover, to better exploit the use of AT-RvD1, we will study the mechanisms by which it activates the ALX/FPR2 using a knock-out mouse for this receptor (ALX/FPR2-/-). Next, we will describe the ALX/FPR2 signaling mechanisms in mouse and human cells. Finally, we will determine whether ALX/FPR2 signaling pathways are altered in minor SG biopsies (both with and without SS), thereby further extending our findings to the human disease. Our overall hypothesis is that healthy SG functioning will be restored by local AT-RvD1 treatment. Aim 1 will demonstrate the benefits of delivering AT-RvD1 locally for restoring SG function. Aim 2 will determine ALX/FPR2 signaling mechanisms and Aim 3 will translate ALX/FPR2 signaling mechanisms to humans.