Post-resolution macrophage-derived lipids shapes long-term tissue immunity and integrity

Resolving inflammation is thought to return the affected tissue back to homeostasis. However, we show that within days following resolution of Streptococcus pneumonia-triggered lung inflammation there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing an alveolar or interstitial phenotype. Transcriptomic analysis revealed that macrophages are enriched with genes that drive T cell chemotaxis and differentiation as well as prostaglandin biosynthesis. Therapeutic depletion of post-resolution macrophages, inhibition of PGE2 synthesis or antagonism of EP4 reduced numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the a-integrin, CD103. This intervention resulted in a failure of these cells to reappear and reactivate upon secondary challenge up to six weeks following primary infection. Concomitantly, EP4 antagonism caused accumulation of lung macrophages and marked tissue fibrosis. Hence, resolving inflammation triggers a second wave of immune activity controlled, in part, by PGE2, which through EP4, drives local tissue-resident T cell development on the one hand, whilst limiting tissue injury on the other Overall design: To understand post-resolution mononuclear phagocyte function and the immuno-biology they control, macrophages bearing an alveolar phenotype as well as the three populations of interstitial macrophages Three populations of interstitial macrophages (Figure 2E-H) were sorted using fluorescence-activated single cell sorting (FACS) from naïve as well as day 14 post S. pneumonia challenged mice and their transcriptomes sequenced using Illumina NovaSeq.