CCR2 mediates increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17.,Mucosal Immunology

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CCR2 mediates increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2018-Nov-29 , DOI: 10.1038/s41385-018-0106-4
Stephen J Gurczynski ₁ , Niket Nathani ₁ , Helen I Warheit-Niemi ₂ , Elissa M Hult ₂ , Amy Podsiad ₁ , Jane Deng _{1,

3} , Rachel L Zemans ₁ , Urvashi Bhan _{1,

4} , Bethany B Moore _{1,

2}

Affiliation

Post influenza bacterial pneumonia is associated with significant mortality and morbidity. Dendritic cells (DCs) play a crucial role in host defense against bacterial pneumonia, but their contribution to post influenza-susceptibility to secondary bacterial pneumonia is incompletely understood. WT and CCR2^-/- mice were infected with 100 plaque forming units (pfu) H1N1 intranasally alone or were challenged on day 5 with 7 × 10⁷ colony forming units (cfu) methicillin-resistant Staphylococcus aureus intratracheally. WT mice express abundant CCL2 mRNA and protein post-H1N1 alone or dual infection. CCR2^-/- mice had significantly higher survival as compared to WT mice, associated with significantly improved bacterial clearance at 24 and 48 h (10-fold and 14-fold, respectively) post bacterial challenge. There was robust upregulation of IL-23 and IL-17 as well as downregulation of IL-27 expression in CCR2^-/- mice following sequential infection as compared to WT mice, which was also associated with significantly greater accumulation of CD103⁺ DC. Finally, WT mice treated with a CCR2 inhibitor showed improved bacterial clearance in association with similar cytokine profiles as CCR2^-/- mice. Thus, CCR2 significantly contributes to increased susceptibility to bacterial infection after influenza pneumonia likely via altered dendritic cell responses and thus, CCR2 antagonism represents a potential therapeutic strategy.

中文翻译：

CCR2 通过限制 IL-17 的树突状细胞诱导来介导对 H1N1 后细菌性肺炎的易感性增加。

流感后细菌性肺炎与显着的死亡率和发病率有关。树突状细胞 (DC) 在宿主防御细菌性肺炎中起着至关重要的作用，但它们对流感后继发性细菌性肺炎易感性的贡献尚不完全清楚。WT 和 CCR2 ^-/-小鼠单独鼻内感染 100 个噬菌斑形成单位 (pfu) H1N1，或在第 5 天气管内接受 7 × 10 ^{7 个}菌落形成单位 (cfu) 耐甲氧西林金黄色葡萄球菌的攻击。WT 小鼠表达丰富的 CCL2 mRNA 和蛋白质后 H1N1 单独或双重感染。CCR2 ^-/-与 WT 小鼠相比，小鼠的存活率明显更高，这与细菌攻击后 24 小时和 48 小时（分别为 10 倍和 14 倍）的细菌清除率显着提高有关。^{与 WT 小鼠相比，连续感染后 CCR2 -/-}小鼠中 IL-23 和 IL-17 的强烈上调以及 IL-27 表达的下调，这也与显着增加的 CD103 ⁺ DC 积累有关。最后，用 CCR2 抑制剂处理的 WT 小鼠显示出与 CCR2 相似的细胞因子谱相关的细菌清除率提高^-/-老鼠。因此，CCR2 可能通过改变树突状细胞反应显着促进流感肺炎后对细菌感染的易感性，因此，CCR2 拮抗作用代表了一种潜在的治疗策略。

更新日期：2019-01-26

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