4.8 Article

CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage

期刊

FRONTIERS IN IMMUNOLOGY
卷 13, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.927213

关键词

irradiation damage; hematopoiesis; intestinal stem cells; macrophage activation; TLR4 activation

资金

  1. Military Research Program [82003388]
  2. National Natural Science Foundation of China [81872559]
  3. [20QNPY063]

向作者/读者索取更多资源

CRX-527, a TLR4 ligand, has been shown to be safer and more effective than LPS in protecting against radiation damage. It induces differentiation of HSCs and promotes the activation of macrophages, which play an important role in immune defense. The protection of the hematopoietic and intestinal systems from radiation damage is achieved through the maintenance of intestinal function, promotion of intestinal stem cell regeneration, and invasion of macrophages from peripheral blood.
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.

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