Burnett School of Biomedical Sciences, University of Central Florida, College of Medicine, Orlando, FL 32827, USA.
Food Funct. 2020 Nov 18;11(11):9526-9534. doi: 10.1039/d0fo02328k.
It is well known that consumption of a high-fat diet (HFD) promotes intestinal inflammation despite little being known about causative factors. Recent evidence implicates dietary peroxidized lipids (POLs), which are typically formed from the oxidation of polyunsaturated fatty acid double bonds, as potential contributors due to their enrichment in HFDs, ability to be formed during gastrointestinal transit, and immunogenic and cytotoxic properties. 13-HPODE, the most common dietary POL, demonstrates pro-inflammatory activity in a variety of immune cells, especially Natural Killer (NK) cells whose role in mediating intestinal inflammation remains unclear. Therefore, we set out to investigate how 13-HPODE and other POLs modulate NK-cell activity in the context of intestinal inflammation. We not only found that NK cells fully decompose exogenous 13-HPODE, but that direct treatment stimulates TNF-α and MCP1 expression as well as Granzyme B (GZMB) secretion in a dose-dependent manner. Similar results were observed upon incubation of NK cells with oxidized, but not-unoxidized, low-density lipoproteins. Secretory products from 13-HPODE-treated NK cells were able to induce Caco2 intestinal cell inflammation in the same way as exogenous GZMB with greater sensitivity in undifferentiated compared to differentiated cells. Results were recapitulated in 13-HPODE-fed mice, demonstrating both spatial and temporal patterns of elevated GZMB expression that favored acute treatments in the distal intestinal epithelium. Collectively, our results suggest that that HFD-derived POLs, like 13-HPODE, potentially contribute to intestinal inflammation by stimulating the secretion of pro-inflammatory granzymes by resident NK cells, ultimately revealing a more direct role for diet in modulating gut homeostasis and the immune environment.
众所周知，尽管人们对致病因素知之甚少，但高脂肪饮食（HFD）会促进肠道炎症。最近的证据表明，膳食过氧化物脂质（POLs）可能是肠道炎症的潜在致病因素，因为它们在 HFD 中含量丰富，能够在胃肠道转运过程中形成，并且具有免疫原性和细胞毒性。13-HPODE 是最常见的膳食 POL，它在各种免疫细胞中表现出促炎活性，尤其是自然杀伤（NK）细胞，其在介导肠道炎症中的作用尚不清楚。因此，我们着手研究 13-HPODE 和其他 POL 如何在肠道炎症的背景下调节 NK 细胞的活性。我们不仅发现 NK 细胞能够完全分解外源性 13-HPODE，而且直接处理会以剂量依赖的方式刺激 TNF-α 和 MCP1 的表达以及颗粒酶 B（GZMB）的分泌。用氧化但未氧化的低密度脂蛋白孵育 NK 细胞也观察到类似的结果。来自用 13-HPODE 处理的 NK 细胞的分泌产物能够以与外源性 GZMB 相同的方式诱导 Caco2 肠道细胞炎症，并且在未分化细胞中比分化细胞更敏感。在 13-HPODE 喂养的小鼠中得到了结果的重现，表明 GZMB 表达的空间和时间模式升高，有利于在远端肠道上皮中进行急性治疗。总的来说，我们的结果表明，HFD 衍生的 POLs，如 13-HPODE，可能通过刺激驻留 NK 细胞分泌促炎颗粒酶来促进肠道炎症，最终揭示了饮食在调节肠道稳态和免疫环境方面更直接的作用。
