Biosynthetic metabolomes of cysteinyl-containing immunoresolvents

[摘要] Resolution of inflammation is an active process regulated by specialized proresolving mediators where we identified 3 new pathways producing allylic epoxide derived mediators that stimulate regeneration [i.e., peptido-conjugates in tissue regeneration (CTRs)]. Here, using self-limited Escherichia coli peritonitis in mice, we identified endogenous maresin (MaR) CTR (MCTR), protectin (PD) CTR (PCTR), and resolvin CTR in infectious peritoneal exudates and distal spleens, as well as investigated enzymes involved in their biosynthesis. PCTRs were identified to be temporally regulated in peritoneal exudates and spleens. PCTR1 and MCTR1 were each produced by human recombinant leukotriene (LT) C-4 synthase (LTC4S) and glutathione S-transferases (GSTs) [microsomal GST (mGST)2, mGST3, and GST-mu(GSTM)4] from their epoxide precursors [16S,17S-epoxy-PD (ePD) and 13S,14-Sepoxy-MaR (eMaR)1, with preference for GSTM4. Both eMaR and ePD inhibited LTB4 production by LTA(4) hydrolase. LTC4S, mGST2, mGST3, and GSTM4 were each expressed in human M1- and M2-like macrophages where LTC4S inhibition increased CTRs. Finally, PCTR1 showed potent analgesic action. These results demonstrate CTR biosynthesis in mouse peritonitis, human spleens, and human macrophages, as well as identification of key enzymes in these pathways. Moreover, targeting LTC4S increases CTR metabolomes, giving a new strategy to stimulate resolution and tissue regeneration.

[发布日期] 2019-12-01

[关键词] PRO-RESOLVING MEDIATORS;TISSUE-REGENERATIVE RESOLVIN;FATTY-ACID SUPPLEMENTATION;GLUTATHIONE-S-TRANSFERASE;LIPID MEDIATORS;DOUBLE-BLIND;RESOLUTION;D1;INFLAMMATION;N-3