Investigating Enzymatic Control of Inflammation Oxo-eicosanoid Synthesis in Live Zebrafish

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Presentation Time: 04:30 PM - 04:45 PM
Abstract ID: 4585 - B

Presenting Author:
Yanan Ma , Research Associate at Mem. Sloan Kettering Cancer Ctr.

Abstract:

Eicosanoids, derived from arachidonic acid (AA), are bioactive lipids with chemokine-like function. While prostaglandin and leukotriene have been extensively studied, the genetics of oxoeicosanoid metabolism remain relatively unexplored. The proto-type oxoeicosanoid 5-KETE is generated from AA by 5-lipoxygenase and the long-elusive redox-sensitive enzyme 5-HEDH. Pure 5-KETE attracts leukocytes in vitro and in vivo via the G-protein coupled receptor OXER1. 5-KETE is induced in response to Ischemic, allergic challenges, and colitis. OXER1 inhibition suppresses neutrophilic inflammation in zebrafish and primate asthma models and frameshift mutations of OXER1 in mucosal tumors suggest a yet undescribed cancer role. However, the lack of OXER1 orthologs in rodents and uncharacterized 5-HEDH enzyme have severely stalled oxoeicosanoid research for the past 30 years. Through a combination of lipidomics, enzymatic activity screening and genetic perturbation in human cell culture, coupled with intravital imaging of acute inflammation in zebrafish, we here identify the first-in-class 5-HEDH member. Its genetic deletion severely compromises 5-KETE synthesis in human cells and abrogates rapid neutrophil and macrophage recruitment to zebrafish tail fin wounds in vivo, indicating its role in neutrophil and macrophage interplay. Our work will open new therapeutic avenues for treating acute and chronic mucosal inflammation.