Human PTGR2 Inactivation Alters Eicosanoid Metabolism and Cytokine Response of Inflammatory Macrophages

Prostaglandin
reductase 2 (PTGR2) regulates inflammatory lipid
signaling through the metabolism of the PGE2 metabolite 15-keto-PGE2. PTGR2 inhibitors have been reported but whether small molecule
inactivation can recapitulate the anti-inflammatory phenotype observed
in PTGR2 knockout systems has not been explored. Here, we disclose
an optimized sulfonyl triazole (SuTEx) inhibitor of human PTGR2 that
blocks biochemical activity by liganding the noncatalytic tyrosines
Y100 and Y265 in the active site. Quantitative and multiplexed chemoproteomics
verified covalent engagement of endogenous PTGR2 in THP1 macrophages
with moderate proteome-wide selectivity. PTGR2 inactivation with the
SuTEx inhibitor resulted in suppression of secreted inflammatory lipids
and TNF-α in lipopolysaccharide (LPS)-stimulated macrophages.
Collectively, our findings identify a potent covalent inhibitor of
human PTGR2 that can serve as a tool compound for exploring lipid
metabolism and signaling in macrophages.