Novel proresolving and tissue‐regenerative resolvin and protectin sulfido‐conjugated pathways

Local mediators orchestrate the host response to both sterile and infectious challenge and resolution. Recent evidence demonstrates that maresin sulfido‐conjugates actively resolve acute inflammation and promote tissue regeneration. In this report, we investigated self‐limited infectious exudates for novel bioactive chemical signals in tissue regeneration and resolution. By use of spleens from Escherichia coli infected mice, self‐resolving infectious exudates, human spleens, and blood from patients with sepsis, we identified 2 new families of potent molecules. Characterization of their physical properties and isotope tracking demonstrated that the bioactive structures contained a docosahexaenoate backbone and sulfido‐conjugated triene or tetraene double‐bond systems. Activated human phagocytes converted 17‐hydro(peroxy)‐4Z,7Z,10Z,13Z,15E,19Z‐docosahexaenoic acid to these bioactive molecules. Regeneration of injured planaria was accelerated with nanomolar amounts of 16‐glutathionyl, 17‐hydroxy‐4Z,7Z,10,12,14,19Z‐docosahexaenoic acid and 16‐cysteinylglycinyl, 17‐hydroxy‐4Z,7Z,10,12,14,19Z‐docosahexaenoic acid (Protectin sulfido‐conjugates) or 8‐glutathionyl, 7,17‐dihydroxy‐4Z,9, 11,13Z,15E,19Z‐docosahexaenoic acid and 8‐cysteinylglycinyl, 7,17‐dihydroxy‐4Z,9,11,13Z, 15E,19Z‐docosahexaenoic acid (Resolvin sulfido‐conjugates). Each protectin and resolvin sulfido‐conjugate dose dependently (0.1‐10 nM) stimulated human macrophage bacterial phagocytosis, phagolysosomal acidification, and efferocytosis. Together, these results identify 2 novel pathways and provide evidence for structural elucidation of new resolution moduli. These resolvin and protectin conjugates identified in mice and human infected tissues control host responses promoting catabasis.—Dalli, J., Ramon, S., Norris, P. C., Colas, R. A., Serhan, C. N. Novel proresolving and tissue‐regenerative resolvin and protectin sulfido‐conjugated pathways. FASEB J. 29, 2120‐2136 (2015). www.fasebj.org

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