Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, 01049-010 São Paulo, Brazil.
Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049-900 São Paulo, Brazil.
Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):E8469-E8478. doi: 10.1073/pnas.1722016115. Epub 2018 Aug 20.
Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-β, PGE, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-β, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic -infected macrophages by dendritic cells triggers PGE production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic -infected cells by dendritic cells promoted high levels of PGE, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.
炎症反应通过清除死亡细胞来终止，这个过程称为细胞吞噬作用。细胞吞噬作用的一个后果是合成抗炎介质 TGF-β、PGE 和 IL-10；然而，被感染细胞的吞噬作用通过引发 TGF-β、IL-6 和 IL-23 的合成而有利于 Th17 反应。最近，我们表明树突状细胞吞噬凋亡感染的巨噬细胞会触发 PGE 的产生，除了产生促 Th17 细胞因子的表达。因此，我们研究了 PGE 在 Th17 分化和肠道病理中的作用。树突状细胞吞噬凋亡感染细胞会促进高水平的 PGE，通过 T 细胞中的 EP4-PKA 途径损害 IL-1R 的表达，从而抑制 Th17 分化。感染小鼠肠道感染的结果取决于 EP4 受体。与用载体对照处理的感染小鼠相比，用 EP4 拮抗剂处理的感染小鼠显示出增强的肠道防御作用。这些结果表明，在感染性结肠炎期间，EP4 信号传导可以作为增强 Th17 免疫和宿主防御的一种方式。
