CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.
CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.
复制标题
CRX-527 诱导 HSC 分化，保护肠上皮免受辐射损伤
DOI：
10.3389/fimmu.2022.927213
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
近年来，Toll样受体（TLR）在辐射损伤中的作用得到了广泛的研究，但大多数TLR配体的高毒性和低疗效的固有缺陷限制了其进一步的临床转化。CRX-527作为一种TLR 4配体，很少被报道具有辐射防护作用。我们证明CRX-527在体内比相同剂量的LPS更安全，并且在体外几乎没有毒性作用。CRX-527的给药将野生型小鼠全身照射（TBI）的存活率提高至100%，但在TLR 4-/-小鼠中没有。在TBI后，CRX-527治疗的小鼠中造血系统损伤显著减轻，并且恢复期加快。此外，CRX-527诱导HSC的分化和CRX-527的刺激显著增加LSK细胞的比例和数量，并促进其分化为巨噬细胞，激活免疫防御。此外，我们提出了造血分化在保护肠道免受辐射损伤中的免疫防御作用，并证实了巨噬细胞通过外周血侵入肠道以保护它们免受辐射损伤。同时，CRX-527可维持肠道功能和内环境稳定，促进肠道干细胞再生，对致死剂量辐射所致的肠道损伤具有保护作用。此外，在小鼠使用后，我们发现CRX-527对照射后的TLR 4-/-小鼠的造血系统和肠道系统没有明显的保护作用。总之，CRX-527诱导HSC分化，保护肠上皮免受辐射损伤。CRX-527诱导HSC分化，保护肠上皮免受辐射损伤。为了评价CRX-527对致死剂量照射小鼠的辐射防护作用，分别在TBI前24小时和2小时腹腔注射CRX-527 0.5mg/kg。CRX-527增加造血干细胞的比例和数量，刺激造血干细胞向巨噬细胞分化，激活巨噬细胞的TLR 4通路。巨噬细胞活化可保护肠道固有细胞免受辐射损伤，促进肠道结构和功能的修复，抑制细胞凋亡和细胞凋亡，减轻电离辐射引起的DNA损伤。CRX-527可能是一种潜在的辐射防护剂。
Recently, Toll-like receptors (TLRs) have been extensively studied in radiation damage, but the inherent defects of high toxicity and low efficacy of most TLR ligands limit their further clinical transformation. CRX-527, as a TLR4 ligand, has rarely been reported to protect against radiation. We demonstrated that CRX-527 was safer than LPS at the same dose in vivo and had almost no toxic effect in vitro. Administration of CRX-527 improved the survival rate of total body irradiation (TBI) to 100% in wild-type mice but not in TLR4-/- mice. After TBI, hematopoietic system damage was significantly alleviated, and the recovery period was accelerated in CRX-527-treated mice. Moreover, CRX-527 induced differentiation of HSCs and the stimulation of CRX-527 significantly increased the proportion and number of LSK cells and promoted their differentiation into macrophages, activating immune defense. Furthermore, we proposed an immune defense role for hematopoietic differentiation in the protection against intestinal radiation damage, and confirmed that macrophages invaded the intestines through peripheral blood to protect them from radiation damage. Meanwhile, CRX-527 maintained intestinal function and homeostasis, promoted the regeneration of intestinal stem cells, and protected intestinal injury from lethal dose irradiation. Furthermore, After the use of mice, we found that CRX-527 had no significant protective effect on the hematopoietic and intestinal systems of irradiated TLR4-/- mice. in conclusion, CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage. CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage. To evaluate the radiation protection effect of CRX-527 on mice irradiated with lethal dose, CRX-527 was intraperitoneally injected with 0.5 mg/kg 24 hours and 2 hours before TBI, respectively. CRX-527 increased the proportion and number of hematopoietic stem cells, stimulated the differentiation of hematopoietic stem cells into macrophages, and activated the TLR4 pathway of macrophages. Macrophages activation protected the inherent cells of the intestines from radiation damage after irradiation, promoted the repair of intestinal structure and function, inhibited apoptosis and pyroptosis, and alleviated DNA damage caused by ionizing radiation. CRX-527 may be a potential radiation protection agent.