FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.
FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.
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DOI：
10.1038/ncomms11314
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发表时间：
2016-04-12
影响因子：
16.6
通讯作者：
Boström PA
中科院分区：
文献类型：
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作者：
Bosma M;Gerling M;Pasto J;Georgiadi A;Graham E;Shilkova O;Iwata Y;Almer S;Söderman J;Toftgård R;Wermeling F;Boström EA;Boström PA
FNDC4 是一种与运动相关肌因子鸢尾素 (FNDC5) 具有高度同源性的分泌因子。在这里，我们报告 Fndc4 在几种小鼠炎症模型以及人类炎症条件下显着上调。具体而言，炎症性肠病患者肠道发炎部位的 FNDC4 水平局部升高。有趣的是，与注射对照蛋白的小鼠相比，在诱导结肠炎的小鼠模型中施用重组FNDC4可显着降低疾病的严重程度。相反，缺乏 Fndc4 的小鼠会出现更严重的结肠炎。 FNDC4 与不同免疫细胞类型的结合分析揭示了与巨噬细胞和单核细胞的强烈且特异性的结合。 FNDC4 体外处理骨髓源性巨噬细胞会导致吞噬作用减少、细胞存活增加并减少促炎趋化因子表达。因此，FNDC4 治疗会导致巨噬细胞活性减弱，同时提高其存活率。因此，我们将 FNDC4 定性为对炎症性肠病和可能的其他炎症性疾病具有直接治疗潜力的因子。 FDNC4 是 FNDC5/irisin（一种由运动诱导的肌因子）的同源物，其特征尚未明确。作者在此表明，FDNC4 可以增加生长因子剥夺中巨噬细胞的存活率，抑制吞噬作用和对 M1 和 M2 极化刺激的转录反应，并保护小鼠免受 DSS 诱导的结肠炎。
FNDC4 is a secreted factor sharing high homology with the exercise-associated myokine irisin (FNDC5). Here we report that Fndc4 is robustly upregulated in several mouse models of inflammation as well as in human inflammatory conditions. Specifically, FNDC4 levels are increased locally at inflamed sites of the intestine of inflammatory bowel disease patients. Interestingly, administration of recombinant FNDC4 in the mouse model of induced colitis markedly reduces disease severity compared with mice injected with a control protein. Conversely, mice lacking Fndc4 develop more severe colitis. Analysis of binding of FNDC4 to different immune cell types reveals strong and specific binding to macrophages and monocytes. FNDC4 treatment of bone marrow-derived macrophages in vitro results in reduced phagocytosis, increased cell survival and reduced proinflammatory chemokine expression. Hence, treatment with FNDC4 results in a state of dampened macrophage activity, while enhancing their survival. Thus, we have characterized FNDC4 as a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases. FDNC4 is a poorly characterized homologue of FNDC5/irisin, a myokine induced by exercise. Here the authors show that FDNC4 increases macrophage survival in growth factor deprivation, inhibits phagocytosis and transcriptional responses to M1 and M2 polarizing stimuli, and protects mice from DSS-induced colitis.