Disrupting endogenous retroelements with a reverse transcriptase inhibitor alleviates DSS-induced colitis in mice

IF 7.9 2区 医学 Q1 IMMUNOLOGY Mucosal Immunology Pub Date : 2024-02-01 DOI:10.1016/j.mucimm.2023.10.004
Yifan Niu , Yu Liu , Xiang Ma , Lu Liu , Sihong Li , Rui Li , Tao Wang , Houhui Song , Dong Niu
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Abstract

Endogenous retroelements play vital roles in sustaining immune homeostasis. Activation of endogenous retroelements can trigger cGAS/STING pathway and downstream pro-inflammatory cytokine production. Activated macrophages (M1), which can be induced by pro-inflammatory cytokines, are involved in the development of colitis. Here we aimed to determine whether a retrovirus reverse transcriptase inhibitor azidothymidine (AZT) could influence M1 macrophage polarization and rescue colitis by inhibiting the reverse transcription of murine endogenous retroelements. A dextran sodium sulfate salt (DSS)-induced colitis mouse model (male C57BL/6N) and a lipopolysaccharides-treated RAW264.7 cell line were used to evaluate the protective role of AZT in colitis alleviation. An upregulated expression of endogenous retroelements was first detected in both the colons of the mice with colitis and the lipopolysaccharides-stimulated M1 cells, and treatment with AZT significantly decreased the expression. Meanwhile, a downregulation of cGAS/STING/NF-κB pathway and pro-inflammatory cytokines that induce M1 macrophage polarization was also observed in AZT-treated colitis or M1 groups. Moreover, the symptoms of DSS-induced colitis could be significantly alleviated by AZT. In summary, the endogenous retroelement inhibitor AZT could rescue the DSS-induced colitis possibly via blocking M1 macrophage polarization through cGAS/STING/NF-κB pro-inflammatory pathway. Thus, a pharmacological blockade of endogenous retroelements would be a new strategy for clinical therapy of colitis.

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用逆转录酶抑制剂干扰内源性逆转录素,可减轻 DSS 诱导的小鼠结肠炎
内源性逆源因子在维持免疫平衡方面发挥着重要作用。激活内源性逆转录酶可触发 cGAS/STING 通路和下游促炎细胞因子的产生。激活的巨噬细胞(M1)可由促炎细胞因子诱导,参与结肠炎的发展。在此,我们旨在确定逆转录病毒逆转录酶抑制剂氮卓胸苷(AZT)是否能通过抑制小鼠内源性逆转录病毒的逆转录来影响 M1 巨噬细胞的极化并挽救结肠炎。研究人员使用葡聚糖硫酸钠盐(DSS)诱导的结肠炎小鼠模型(雄性 C57BL/6N)和脂多糖处理的 RAW264.7 细胞系来评估 AZT 在缓解结肠炎方面的保护作用。首先在结肠炎小鼠的结肠和脂多糖刺激的 M1 细胞中都检测到了内源性逆转录酶的上调表达,而用 AZT 治疗可显著降低其表达。同时,在 AZT 治疗的结肠炎组或 M1 组中,还观察到 cGAS/STING/NF-κB 通路和诱导 M1 巨噬细胞极化的促炎细胞因子的下调。此外,AZT 还能显著缓解 DSS 诱导的结肠炎症状。综上所述,内源性逆转录酶抑制剂 AZT 可通过 cGAS/STING/NF-κB 促炎途径阻断 M1 巨噬细胞极化,从而缓解 DSS 诱导的结肠炎。因此,药物阻断内源性逆转录酶将成为临床治疗结肠炎的新策略。
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上海源叶 AZT
¥29.00~¥22220.00
阿拉丁 C-176
¥297.00~¥8400.00
索莱宝 LPS
索莱宝 penicillin/streptomycin
来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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