Nocardia rubra cell-wall skeleton mitigates whole abdominal irradiation-induced intestinal injury via regulating macrophage function

Lingling Wu; Long Chen; Huijuan Li; Yawei Wang; Kexin Xu; Wanchao Chen; Aihua Zhang; Yu Wang; Chunmeng Shi

doi:10.1093/burnst/tkad045

Nocardia rubra cell-wall skeleton mitigates whole abdominal irradiation-induced intestinal injury via regulating macrophage function

Burns Trauma. 2024 Mar 4:12:tkad045. doi: 10.1093/burnst/tkad045. eCollection 2024.

Authors

Lingling Wu^{1

2}, Long Chen², Huijuan Li², Yawei Wang², Kexin Xu^{2

3}, Wanchao Chen², Aihua Zhang¹, Yu Wang², Chunmeng Shi^{1

2}

Affiliations

¹ Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, China.
² State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China.
³ College of Biological Engineering, Chongqing University 400044, Chongqing, China.

Abstract

Background: Ionizing radiation (IR)-induced intestinal injury is a major side effect and dose-limiting toxicity in patients receiving radiotherapy. There is an urgent need to identify an effective and safe radioprotectant to reduce radiation-induced intestinal injury. Immunoregulation is considered an effective strategy against IR-induced injury. The purpose of this article was to investigate the protective effect of Nocardia rubra cell wall skeleton (Nr-CWS), an immunomodulator, on radiation-induced intestinal damage and to explore its potential mechanism.

Methods: C57BL/6 J male mice exposed to 12 Gy whole abdominal irradiation (WAI) were examined for survival rate, morphology and function of the intestine and spleen, as well as the gut microbiota, to comprehensively evaluate the therapeutic effects of Nr-CWS on radiation-induced intestinal and splenetic injury. To further elucidate the underlying mechanisms of Nr-CWS-mediated intestinal protection, macrophages were depleted by clodronate liposomes to determine whether Nr-CWS-induced radioprotection is macrophage dependent, and the function of peritoneal macrophages stimulated by Nr-CWS was detected in vitro.

Results: Our data showed that Nr-CWS promoted the recovery of intestinal barrier function, enhanced leucine-rich repeat-containing G protein-coupled receptor 5⁺ intestinal stem cell survival and the regeneration of intestinal epithelial cells, maintained intestinal flora homeostasis, protected spleen morphology and function, and improved the outcome of mice exposed to 12 Gy WAI. Mechanistic studies indicated that Nr-CWS recruited macrophages to reduce WAI-induced intestinal damage. Moreover, macrophage depletion by clodronate liposomes blocked Nr-CWS-induced radioprotection. In vitro, we found that Nr-CWS activated the nuclear factor kappa-B signaling pathway and promoted the phagocytosis and migration ability of peritoneal macrophages.

Conclusions: Our study suggests the therapeutic effect of Nr-CWS on radiation-induced intestinal injury, and provides possible therapeutic strategy and potential preventive and therapeutic drugs to alleviate it.

Keywords: Intestinal flora; Ionizing radiation; Nocardia rubra cell wall skeleton; Peritoneal macrophages; Radiation protection; Radiation-induced intestinal injury.