Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Immun Inflamm Dis. 2021 Sep;9(3):891-904. doi: 10.1002/iid3.445. Epub 2021 May 4.
Salmonella spp. are a recognized and global cause of serious health issues from gastroenteritis to invasive disease. The mouse model of human typhoid fever, which uses Salmonella enterica serovar Typhimurium (STM) in susceptible mouse strains, has revealed that the bacteria gain access to extraintestinal tissues from the gastrointestinal tract to cause severe systemic disease. Previous analysis of the immune responses against Salmonella spp. revealed the crucial role played by dendritic cells (DCs) in carrying STM from the intestinal mucosa to the mesenteric lymph nodes (mLNs), a key site for antigen presentation and T cell activation. In this study, we investigated the influence of chemokine CCL17 on the dissemination of STM.
WT, CCL17/EGFP reporter, or CCL17-deficient mice were infected orally with STM (SL1344) or mCherry-expressing STM for 1-3 days. Colocalization of STM with CCL17-expressing DCs in Peyer's patches (PP) and mLN was analyzed by fluorescence microscopy. In addition, DCs and myeloid cell populations from naïve and Salmonella-infected mice were analyzed by flow cytometry. Bacterial load was determined in PP, mLN, spleen, and liver 1 and 3 days after infection.
Histological analysis revealed that CCL17-expressing cells are located in close proximity to STM in the dome area of PP. We show that, in mLN, STM were preferentially located within CCL17 rather than CCL17 DCs, besides other mononuclear phagocytes, and identified the CD103 CD11b DC subset as the main STM-carrying DC population in the intestine. STM infection triggered upregulation of CCL17 expression in specific intestinal DC subsets in a tissue-specific manner. The dissemination of STM from the gut to the mLN, however, was only moderately influenced by the presence of CCL17.
CCL17-expressing DCs were preferentially infected by Salmonella in the intestine in comparison to other DC. Nevertheless, the production of CCL17 was not essential for the early dissemination of Salmonella from the gut to systemic organs.
沙门氏菌是一种公认的全球性致病菌，可引起从肠胃炎到侵袭性疾病等严重健康问题。使用鼠伤寒沙门氏菌（STM）的人类伤寒鼠模型揭示了细菌从胃肠道进入肠道外组织，从而导致严重的全身疾病。先前对沙门氏菌免疫反应的分析表明，树突状细胞（DCs）在将 STM 从肠黏膜运送到肠系膜淋巴结（mLN）中发挥了关键作用，mLN 是抗原呈递和 T 细胞激活的关键部位。在这项研究中，我们研究了趋化因子 CCL17 对 STM 传播的影响。
用 STM（SL1344）或表达 mCherry 的 STM 经口感染 WT、CCL17/EGFP 报告基因或 CCL17 缺陷型小鼠 1-3 天。用荧光显微镜分析 PP 和 mLN 中 STM 与表达 CCL17 的 DC 的共定位。此外，用流式细胞术分析未感染和感染沙门氏菌的小鼠的 DC 和髓样细胞群。感染后 1 天和 3 天，测定 PP、mLN、脾和肝中的细菌负荷。
组织学分析表明，CCL17 表达细胞位于 PP 穹顶区的 STM 附近。我们发现，在 mLN 中，STM 主要位于 CCL17 内，而不是 CCL17 DC 内，除其他单核吞噬细胞外，还鉴定出 CD103 CD11b DC 亚群是肠道中主要的携带 STM 的 DC 群体。STM 感染以组织特异性方式诱导特定肠道 DC 亚群中 CCL17 的表达上调。然而，CCL17 的存在仅适度影响 STM 从肠道向 mLN 的传播。
与其他 DC 相比，CCL17 表达的 DC 在肠道中优先被沙门氏菌感染。然而，CCL17 的产生对于沙门氏菌从肠道向全身器官的早期传播并不是必需的。
