Intelectin1 ameliorates macrophage activation via inhibiting the nuclear factor kappa B pathway
Intelectin1 ameliorates macrophage activation via inhibiting the nuclear factor kappa B pathway
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DOI：
10.1507/endocrj.ej21-0438
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发表时间：
2021-12-03
影响因子：
2
通讯作者：
Furuya, Fumihiko
中科院分区：
文献类型：
--
作者：
Kobayashi, Hidetoshi;Uchimura, Kohei;Furuya, Fumihiko
Inteletin1(Itln1)是一种脂肪因子，在肠道、卵巢和肺中大量表达。在糖尿病或肥胖症患者中，ITLN1的表达水平降低，但其产生和功能的机制仍存在争议。本研究旨在阐明ITLN1合成及其相关巨噬细胞活化的机制。为分析高脂高糖饮食对肠道ITLN1基因表达的影响，给小鼠灌胃高脂高糖饮食8周。饲喂HFHCD可增强肠道内质网应激，抑制肠道内分泌细胞Itln1的表达，降低循环中ITLN1水平。相反，给予化学伴侣的治疗和减少内质网应激可以恢复喂食HFHCD的小鼠肠道中Itln1的表达。此外，体外研究表明，ITLN1与脂联素受体1在物理上相互作用，并通过抑制巨噬细胞中的核因子kappa B信号通路，抑制内毒素诱导的促炎细胞因子的mRNA表达和吞噬活性。这些结果表明，饮食诱导的内质网应激通过抑制肠道中ITLN1的合成来减少循环中的ITLN1，而循环中的ITLN1的减少可能会增强促炎症细胞因子的表达和巨噬细胞的激活，从而加剧代谢综合征的慢性炎症。
Inteletin1 (Itln1) is an adipokine that is abundantly expressed in intestine, ovary, and lung. The expression levels of ITLN1 are decreased in the presence of diabetes or obesity, but the mechanisms of its production and function are still controversial. The aim of this study is to elucidate the mechanisms of ITLN1 synthesis and ITLN1-associated macrophage activation. To analyze the effects of high fat and high-carbohydrate diet (HFHCD) on the expression of ITLN1 in the intestine, the mice were fed a HFHCD for 8 weeks. HFHCD feeding enhanced the endoplasmic reticulum (ER)-stress in the intestine and inhibited the expression of Itln1 in the intestinal endocrine cells and lowered circulating ITLN1 levels. In contrast, treatment with a chemical chaperone and reduction of ER-stress restored the expression of Itln1 in the intestine of HFHCD-fed mice. Furthermore, in vitro studies indicated that ITLN1 physically interacts with adiponectin receptor 1 and suppresses lipopolysaccharide-induced mRNA expressions of pro-inflammatory cytokines and phagocytosis activities via inhibition of the nuclear factor kappa B-signaling pathway in macrophages. These results suggest that diet-induced ER-stress decreases circulating ITLN1 via inhibition of its synthesis in the intestine, and a reduction of circulating ITLN1 might enhanced the expression of proinflammatory cytokines and macrophage activation, following exacerbate the chronic inflammation of metabolic syndrome.