Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model
Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model
复制标题
DOI：
10.1172/jci123700
复制
发表时间：
2019-09-03
影响因子：
15.9
通讯作者：
Reddy, Srinivasa T.
中科院分区：
文献类型：
--
作者：
Meriwether, David;Sulaiman, Dawoud;Reddy, Srinivasa T.
环加氧酶 2 (Cox2) 全基因敲除和髓系基因敲除 (MKO) 小鼠在喂食含胆酸盐的高脂饮食 (CCHF) 时会出现克罗恩病样肠道炎症。我们证明，CCHF 损害肠道屏障功能并增加内毒素的易位，在 Cox2-KO 小鼠中引发 TLR/MyD88 依赖性炎症，但在 WT 小鼠中则不然。 Cox2-MKO 增加了 LPS 激活的巨噬细胞以及 CCHF 攻击后肠道组织和血浆中的促炎介质。 Cox2-MKO 还可以减少肠道组织中解脂素 A4 (LXA4) 的炎症，而给予 LXA4 类似物可以挽救喂食 CCHF 的 Cox2-MKO 小鼠的疾病。载脂蛋白 A-I (APOA1) 模拟物 4F 减轻了 Cox2-MKO/CCHF 和吡罗昔康加速 II(10-/-) 炎症性肠病 (IBD) 模型中的疾病，并降低了组织和血浆中升高的促炎介质水平。 APOA1 模拟 Tg6F 疗法在 Cox2-MKO/CCHF 模型中也能有效减少肠道炎症。我们进一步证明APOA1模拟肽（a）抑制人巨噬细胞和肠上皮中的LPS和氧化1-棕榈酰-2-花生四烯酰-sn-磷脂酰胆碱依赖性（oxPAPC依赖性）促炎反应，以及（b）直接清除小鼠肠道组织和血浆中的促炎脂质。我们的结果支持促炎和消炎脂质在 IBD 病理学中的因果作用以及 APOA1 模拟肽治疗 IBD 的转化潜力。
Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high-fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2-KO but not WT mice. Cox2-MKO increased proinflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2-MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, whereas administration of an LXA4 analog rescued disease in Cox2-MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2-MKO/CCHF and piroxicam-accelerated Il(10-/-) models of inflammatory bowel disease (IBD) and reduced elevated levels of proinflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2-MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides (a) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine-dependent (oxPAPC-dependent) proinflammatory responses in human macrophages and intestinal epithelium, and (b) directly cleared proinflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for proinflammatory and inflammation-resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.