IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection
IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection
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DOI：
10.1016/j.chom.2016.06.008
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发表时间：
2016-08-10
影响因子：
30.3
通讯作者：
Hardt, Wolf-Dietrich
中科院分区：
文献类型：
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作者：
Dolowschiak, Tamas;Mueller, Anna Angelika;Hardt, Wolf-Dietrich
鼠伤寒沙门氏菌（S. Tm）引起急性肠病，4-7天后消退。引人注目的是，抗生素治疗并不能加速疾病的消退。我们使用S. Tm小肠结肠炎模型筛选阻断缓解的因素。抗生素环丙沙星在3-24小时内清除病原体粪便负荷，而肠道病理消退较慢（Psi(50)：类似于48小时，缓解期：6-9天）。这种延迟消退是由干扰素- γ (ifn - γ)依赖性反应介导的，该反应在急性感染期间触发并持续整个治疗过程。具体来说，粘膜T细胞和NK细胞产生的ifn - γ通过维持转录调节因子STAT1的信号传导和促进炎症介质如IL-1 β、TNF和iNOS的表达来延缓疾病的解决。此外，持续的ifn - γ促进吞噬细胞积累，阻碍IL-22和凝集素REGIII β介导的抗菌防御。这些发现揭示了ifn - γ在延缓肠道炎症消退中的作用，并可能为急性沙门氏菌肠病、慢性炎症性肠病或抗生素治疗期间疾病消退的治疗提供信息。
Salmonella Typhimurium (S. Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S. Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (Psi(50): similar to 48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-gamma (IFN-gamma)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-gamma production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1 beta, TNF, and iNOS. Additionally, sustained IFN-gamma fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIII beta. These findings reveal a role for IFN-gamma in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.