Laboratory of Applied Mechanobiology, Institute of Translational Medicine, Department for Health Sciences and Technology (D-HEST), ETH Zurich , Vladimir-Prelog-Weg 4, HCI F443 CH-8093 Zürich, Switzerland.
Nano Lett. 2018 Jan 10;18(1):15-25. doi: 10.1021/acs.nanolett.7b01617. Epub 2017 Dec 28.
Since evidence is rising that extracellular matrix (ECM) fibers might serve as reservoirs for growth factors and cytokines, we investigated the interaction between fibronectin (FN) and interleukin-7 (IL-7), a cytokine of immunological significance and a target of several immunotherapies. By employing a FN fiber stretch assay and Förster resonance energy transfer (FRET) confocal microscopy, we found that stretching of FN fibers increased IL-7 binding. We localized the FN binding site on the CD loop of IL-7, since a synthetic CD loop peptide also bound stronger to stretched than to relaxed FN fibers. On the basis of a structural model, we propose that the CD loop can bind to FN, while IL-7 is bound to its cognate cell surface receptors. Sequence alignment with bacterial adhesins, which also bind the FN N-terminus, suggests that a conserved motif on the CD loop (TKSLEEN and the truncated SLEE in human and mouse IL-7, respectively) might bind to the second FN type I module (FnI) and that additional epitopes enhance the stretch-upregulated binding. FN fiber stretching might thus serve as a mechano-regulated mechanism to locally concentrate IL-7 in an ECM-bound state, thereby upregulating the potency of IL-7 signaling. A feedback model mechanism is proposed that could explain the well-known, but poorly understood, function of IL-7 in ECM homeostasis. Understanding how local IL-7 availability and signaling might be modulated by the tensional state of the ECM niche, which is adjusted by residing stroma cells, is highly relevant for basic science but also for advancing IL-7 based immunotherapies.
由于越来越多的证据表明细胞外基质 (ECM) 纤维可能作为生长因子和细胞因子的储存库，我们研究了纤维连接蛋白 (FN) 和白细胞介素-7 (IL-7) 之间的相互作用，IL-7 是一种具有免疫意义的细胞因子，也是几种免疫疗法的靶点。通过采用 FN 纤维拉伸测定法和Förster 共振能量转移 (FRET) 共聚焦显微镜，我们发现拉伸 FN 纤维会增加 IL-7 的结合。我们将 FN 的结合位点定位在 IL-7 的 CD 环上，因为合成的 CD 环肽与拉伸的 FN 纤维的结合也比与松弛的 FN 纤维的结合更强。基于结构模型，我们提出 CD 环可以与 FN 结合，而 IL-7 则与它的同源细胞表面受体结合。与细菌黏附素（也与 FN N 端结合）的序列比对表明，CD 环上的保守基序（人 IL-7 和鼠 IL-7 中的 TKSLEEN 和截短的 SLEE）可能与第二个 FN Ⅰ型模块（FnI）结合，并且额外的表位增强拉伸上调结合。因此，FN 纤维拉伸可能作为一种机械调节机制，将 IL-7 局部集中在 ECM 结合状态，从而上调 IL-7 信号转导的效力。提出了一种反馈模型机制，可以解释 IL-7 在 ECM 动态平衡中的众所周知但理解不足的功能。了解局部 IL-7 可用性和信号转导如何通过 ECM 生态位的紧张状态进行调节，这是由驻留基质细胞调节的，这对于基础科学非常重要，对于推进基于 IL-7 的免疫疗法也非常重要。
