PDF(Pubmed)
Abstract：
Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.
摘要：
解决炎症被认为使受影响的组织恢复到同质性，但最近的证据支持涉及延长免疫活动阶段的非线性解决模型。在这里，我们显示在肺炎链球菌触发的肺部炎症消退后的几天内，具有记忆和组织固有表型的抗原特异性淋巴细胞以及具有肺泡或间质表型的巨噬细胞大量涌入。这些巨噬细胞的转录组显示与前列腺素生物合成相关的基因和驱动T细胞趋化性和分化的基因的富集。解决后巨噬细胞的治疗性消耗，抑制前列腺素E2（PGE2）合成或用EP4拮抗剂治疗，MF498，减少肺CD4+/CD44+/CD62L+和CD4+/CD44+/CD62L-/CD27+T细胞的数量以及它们的α-整合素的表达，CD103.在初次感染后长达六周的二次攻击后，T细胞无法重新出现并重新激活。同时，通过MF498的EP4拮抗作用导致肺巨噬细胞的积累和明显的组织纤维化。因此，我们的研究表明，PGE2信号，主要通过EP4，在炎症消退后的第二波免疫活动中起重要作用。这种次级免疫激活驱动局部组织驻留的T细胞发育,同时限制组织损伤。
