State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Department of Gynecology and Obstetrics, Bethune International Peace Hospital, Shijiazhuang, China.
Front Immunol. 2022 Sep 20;13:900755. doi: 10.3389/fimmu.2022.900755. eCollection 2022.
Specific therapeutics are not available for acute lung injury (ALI) induced by ricin toxin (RT). Inhibiting the host immune response in the course of pulmonary ricinosis is hypothesized to be of benefit and can be achieved by impairing granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, thereby reducing the pro-inflammatory response to exogenous foreign body invasion. However, it is unknown whether mice with impaired GM-CSF signaling can survive after RT inhalation. To test this, colony stimulating factor 2 receptor alpha () knockout (KO) mice that lack GM-CSF signaling and wild-type (WT) mice models of intratracheal exposure to a lethal dose (2× LD) of RT were established. Survival was greater in KO mice 21 days after RT inhalation compared with WT mice. Highly co-expressed genes that probably attenuated the pro-inflammatory response in the lung of KO mice were identified. Bioinformatics analysis revealed that transcriptome changes involved mostly inflammation-related genes after RT exposure in both KO mice and WT mice. However, the activity levels of pro-inflammatory pathways, such as the TNF signaling pathway and NF-κB signaling pathway, in KO mice were significantly decreased and the degree of neutrophil chemotaxis and recruitment inhibited after RT-exposure relative to WT mice. RT-qPCR and flow cytometry validated results of RNA-Seq analysis. This work provides potential avenues for host-directed therapeutic applications that can mitigate the severity of ALI-induced by RT.
目前尚无针对蓖麻毒素（RT）引起的急性肺损伤（ALI）的特效疗法。在肺 ricinosis 过程中抑制宿主免疫反应被认为是有益的，可以通过损害粒细胞-巨噬细胞集落刺激因子（GM-CSF）信号传导来实现，从而减少对外来异物入侵的促炎反应。然而，GM-CSF 信号受损的小鼠在吸入 RT 后是否能够存活尚不清楚。为了验证这一点，建立了缺乏 GM-CSF 信号的集落刺激因子 2 受体 alpha（CSF2RA）敲除（KO）小鼠和经气管内暴露于致死剂量（2×LD）RT 的野生型（WT）小鼠模型。与 WT 小鼠相比，在 RT 吸入后 21 天，KO 小鼠的存活率更高。鉴定出可能减弱 KO 小鼠肺部促炎反应的高度共表达基因。生物信息学分析表明，在 RT 暴露后，KO 小鼠和 WT 小鼠的转录组变化主要涉及与炎症相关的基因。然而，与 WT 小鼠相比，KO 小鼠中促炎途径（如 TNF 信号通路和 NF-κB 信号通路）的活性水平显著降低，并且在 RT 暴露后中性粒细胞趋化和募集的程度受到抑制。RT-qPCR 和流式细胞术验证了 RNA-Seq 分析的结果。这项工作为宿主导向的治疗应用提供了潜在途径，可以减轻 RT 引起的 ALI 的严重程度。
