Postgraduate Training Base of the People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Jinzhou Medical University, Beijing, China.
People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China.
Front Immunol. 2022 Aug 30;13:927213. doi: 10.3389/fimmu.2022.927213. eCollection 2022.
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 and had almost no toxic effect . 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.
最近，Toll 样受体（TLRs）在辐射损伤中得到了广泛的研究，但大多数 TLR 配体毒性高、疗效低的固有缺陷限制了它们的进一步临床转化。CRX-527 作为 TLR4 配体，很少有报道其具有辐射防护作用。我们证明，在相同剂量下，CRX-527 比 LPS 更安全，几乎没有毒性作用。CRX-527 的给药可将全身照射（TBI）野生型小鼠的存活率提高到 100%，但不能提高 TLR4 敲除小鼠的存活率。TBI 后，CRX-527 治疗组造血系统损伤明显减轻，恢复时间加快。此外，CRX-527 诱导 HSCs 分化，CRX-527 的刺激显著增加了 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，并证实巨噬细胞通过外周血侵入肠道，以防止其受到辐射损伤。同时，CRX-527 维持肠道功能和内稳态，促进肠干细胞再生，保护肠道免受致死剂量照射的损伤。此外，在使用小鼠后，我们发现 CRX-527 对辐射 TLR4-/-小鼠的造血和肠道系统没有明显的保护作用。总之，CRX-527 诱导 HSCs 分化，保护肠道上皮免受辐射损伤。
