Motwani Madhur P, Newson Justine, Kwong Simon, Richard-Loendt Angela, Colas Romain, Dalli Jesmond, Gilroy Derek W
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom.
Division of Neuropathology and, Dept. of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, United Kingdom.
PLoS One. 2017 Oct 26;12(10):e0186964. doi: 10.1371/journal.pone.0186964. eCollection 2017.
Acute inflammation is an immediate response to infection and injury characterised by the influx of granulocytes followed by phagocytosing mononuclear phagocytes. Provided the antigen is cleared and the immune system of the host is fully functional, the acute inflammatory response will resolve. Until now it is considered that resolution then leads back to homeostasis, the physiological state tissues experienced before inflammation occurred. Using a human model of acute inflammation driven by intradermal UV killed Escherichia coli, we found that bacteria and granulocyte clearance as well as pro-inflammatory cytokine catabolism occurred by 72h. However, following a lag phase of about 4 days there was an increase in numbers of memory T cells and CD163+ macrophage at the post-resolution site up to day 17 as well as increased biosynthesis of cyclooxygenase-derived prostanoids and DHA-derived D series resolvins. Inhibiting post-resolution prostanoids using naproxen showed that numbers of tissue memory CD4 cells were under the endogenous control of PGE2, which exerts its suppressive effects on T cell proliferation via the EP4 receptor. In addition, we re-challenged the post-resolution site with a second injection of E. coli, which when compared to saline controls resulted in primarily a macrophage-driven response with comparatively fewer PMNs; the macrophage-dominated response was reversed by cyclooxygenase inhibition. Re-challenge experiments were also carried out in mice where we obtained similar results as in humans. Therefore, we report that acute inflammatory responses in both humans and rodents do not revert back to homeostasis, but trigger a hitherto unappreciated sequence of immunological events that dictate subsequent immune response to infection.
急性炎症是对感染和损伤的即时反应，其特征是粒细胞流入，随后是吞噬性单核吞噬细胞。如果抗原被清除且宿主的免疫系统功能完全正常，急性炎症反应将会消退。到目前为止，人们认为炎症消退后会恢复到内环境稳态，即炎症发生前组织所处的生理状态。利用由皮内注射紫外线灭活的大肠杆菌驱动的人类急性炎症模型，我们发现细菌和粒细胞在72小时内被清除，促炎细胞因子也发生分解代谢。然而，在大约4天的延迟期后，直到第17天，炎症消退部位的记忆T细胞和CD163 +巨噬细胞数量增加，同时环氧化酶衍生的前列腺素和DHA衍生的D系列消退素的生物合成也增加。使用萘普生抑制炎症消退后的前列腺素显示，组织记忆CD4细胞的数量受PGE2的内源性控制，PGE2通过EP4受体对T细胞增殖发挥抑制作用。此外，我们对炎症消退部位再次注射大肠杆菌进行重新刺激，与生理盐水对照组相比，这主要引发了以巨噬细胞为主导的反应，中性粒细胞相对较少；环氧化酶抑制可逆转巨噬细胞主导的反应。我们也在小鼠身上进行了重新刺激实验，得到了与人类相似的结果。因此，我们报告称，人类和啮齿动物的急性炎症反应不会恢复到内环境稳态，而是会触发一系列迄今未被认识到的免疫事件，这些事件决定了随后对感染的免疫反应。
