Production of specialized proresolving mediators (SPMs) during the resolution phase in the acute inflammatory response is key to orchestrating complete resolution. Here, we uncovered a trihydroxy resolvin in fresh human saliva. We identified and determined its complete stereochemistry as 7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid (17R-RvD2) using total organic synthesis and matching of physical properties. The 17R-RvD2 was produced by activated human M2-like macrophages, M1-like macrophages, and human peripheral blood monocytes. 17R-RvD2 displayed potent proresolving functions (picomolar to nanomolar). Topical application of 17R-RvD2 on mouse ear skin reduced neutrophilic infiltration (~50%). 17R-RvD2 increased M2 markers CD206 and CD163 on human monocyte-derived macrophages and enhanced efferocytosis of senescent red blood cells by M2-like macrophages (EC ~ 2.6 × 10 M). In addition, 17R-RvD2 activated the RvD2 receptor and was equipotent to its epimer RvD2. 17R-RvD2 also significantly increased phagocytosis of by human neutrophils. Together, these results establish the complete stereochemistry and potent proresolving functions of the previously unknown 17R-RvD2.
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