Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, CA, USA.
Scand J Gastroenterol. 2021 Jul;56(7):791-805. doi: 10.1080/00365521.2021.1917650. Epub 2021 May 3.
Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium. We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly regulation of ISCs in the crypt niche. We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.
在炎症损伤后，受损的黏膜表面需要多种再生机制来恢复，而这些机制仍未得到很好的定义。此前，我们已经证明三叶因子 3（Trefoil Factor 3，TFF3）的修复作用依赖于神秘受体富含亮氨酸重复和免疫球蛋白样结构域的神经生长抑制因子受体 2（Leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2，LINGO2）。本研究在肠道组织损伤的背景下研究了相关的孤儿受体 LINGO3，以确定 LINGO 家族成员是否普遍对黏膜伤口愈合和维持肠干细胞（intestinal stem cell，ISC）龛所必需的黏膜上皮更新具有重要作用。我们发现 LINGO3 在人类肠细胞上广泛表达，而在含有 ISC 的隐窝龛中则稀疏表达。功能丧失研究表明，LINGO3 参与了葡聚糖硫酸钠（dextran sodium sulfate，DSS）诱导的结肠炎后正常肠道结构的恢复，并且 LINGO3 是长效 TFF2 融合蛋白（TFF2-Fc）治疗作用所必需的，包括许多对细胞增殖和伤口修复至关重要的信号通路。然而，LINGO3-TFF2 蛋白-蛋白相互作用相对较弱，并且 LINGO3 仅部分负责 TFF2 诱导的丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号传导，表明受体复合物中存在其他未识别的成分。然而，无论是 TFF2 还是 LINGO3 的缺乏都会破坏肠类器官的出芽/生长，并降低肠 ISC 基因富含亮氨酸重复的 G 蛋白偶联受体 5（leucine-rich repeat-containing G-protein coupled receptor 5，LGR5）的表达，表明这些蛋白在组织再生中具有同源作用，可能是调节隐窝龛中的 ISC。我们提出，LINGO3 在促进黏膜伤口愈合中发挥了以前未被认识到的作用。
