PDn-3 DPA Pathway Regulates Human Monocyte Differentiation and Macrophage Function,Cell Chemical Biology

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PDn-3 DPA Pathway Regulates Human Monocyte Differentiation and Macrophage Function
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-05-24 , DOI: 10.1016/j.chembiol.2018.04.017
Kimberly Pistorius ₁ , Patricia R Souza ₁ , Roberta De Matteis ₁ , Shani Austin-Williams ₁ , Karoline G Primdahl ₂ , Anders Vik ₂ , Francesca Mazzacuva ₁ , Romain A Colas ₁ , Raquel M Marques ₁ , Trond V Hansen ₂ , Jesmond Dalli ₁

Affiliation

Macrophages are central in orchestrating the clearance of apoptotic cells and cellular debris during inflammation, with the mechanism(s) regulating this process remaining of interest. Herein, we found that the n-3 docosapentaenoic acid-derived protectin (PDn-3 DPA) biosynthetic pathway regulated the differentiation of human monocytes, altering macrophage phenotype, efferocytosis, and bacterial phagocytosis. Using lipid mediator profiling, human primary cells and recombinant enzymes we found that human 15-lipoxygenases initiate the PDn-3 DPApathway catalyzing the formation of an allylic epoxide. The complete stereochemistry of this epoxide was determined using stereocontrolled total organic synthesis as 16S,17S-epoxy-7Z,10Z,12E,14E,19Z-docosapentaenoic acid (16S,17S-ePDn-3 DPA). This intermediate was enzymatically converted by epoxide hydrolases to PD1n-3 DPAand PD2n-3 DPA, with epoxide hydrolase 2 converting 16S,17S-ePDn-3 DPAto PD2n-3 DPAin human monocytes. Taken together these results establish the PDn-3 DPAbiosynthetic pathway in human monocytes and macrophages and its role in regulating macrophage resolution responses.

中文翻译：

PDn-3 DPA 通路调节人单核细胞分化和巨噬细胞功能

巨噬细胞在炎症过程中协调清除凋亡细胞和细胞碎片的核心，调节这一过程的机制仍然令人感兴趣。在这里，我们发现 n-3 二十二碳五烯酸衍生的保护素 (PDn-3 DPA) 生物合成途径调节人类单核细胞的分化，改变巨噬细胞表型、胞吐作用和细菌吞噬作用。使用脂质介质分析、人类原代细胞和重组酶，我们发现人类 15-脂氧合酶启动 PDn-3 DPA 通路，催化烯丙基环氧化物的形成。该环氧化物的完整立体化学是使用立体控制的总有机合成方法确定的 16S,17S-epoxy-7Z,10Z,12E,14E,19Z-二十二碳五烯酸 (16S,17S-ePDn-3 DPA)。该中间体通过环氧化物水解酶酶促转化为 PD1n-3 DPA 和 PD2n-3 DPA，其中环氧化物水解酶 2 在人单核细胞中将 16S、17S-ePDn-3 DPA 转化为 PD2n-3 DPA。综上所述，这些结果确定了人类单核细胞和巨噬细胞中的 PDn-3 DPA 生物合成途径及其在调节巨噬细胞分解反应中的作用。

更新日期：2018-06-22

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