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Biosynthetic metabolomes of cysteinyl‐containing immunoresolvents
Author(s) -
Jouvene Charlotte C.,
Shay Ashley E.,
Soens Mieke A.,
Norris Paul C.,
Haeggström Jesper Z.,
Serhan Charles N.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902003r
Subject(s) - chemistry , biosynthesis , biochemistry , enzyme
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 (LTC 4 S) and glutathione S‐transferases (GSTs) [microsomal GST (mGST)2, mGST3, and GST‐μ (GSTM)4] from their epoxide precursors [16 S ,17 S ‐epoxy‐PD (ePD) and 13 S ,14 S ‐epoxy‐MaR (eMaR)], with preference for GSTM4. Both eMaR and ePD inhibited LTB4 production by LTA 4 hydrolase. LTC 4 S, mGST2, mGST3, and GSTM4 were each expressed in human M1‐ and M2‐like macrophages where LTC 4 S 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 LTC 4 S increases CTR metabolomes, giving a new strategy to stimulate resolution and tissue regeneration.—Jouvene, C. C., Shay, A. E., Soens, M. A., Norris, P. C., Haeggström, J. Z., Serhan, C. N. Biosynthetic metabolomes of cysteinyl‐containing immunoresolvents. FASEB J. 33, 13794‐13807 (2019). www.fasebj.org