an anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury
Denans, N.; Tran, N. T. T.; Swall, M. E.; Diaz, D. C.; Blanck, J.; Piotrowski, T.
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Macrophages are essential for tissue repair and regeneration. Yet, the molecular programs, as well as the timing of their activation during and after tissue injury are poorly defined. Using a high spatio-temporal resolution single cell analysis of macrophages coupled with live imaging after sensory hair cell death in zebrafish, we find that the same population of macrophages transitions through a sequence of three major anti-inflammatory activation states. Macrophages first show a signature of glucocorticoid activation, then IL10 signaling and finally the induction of oxidative phosphorylation by IL4/Polyamine signaling. Importantly, loss-of-function of glucocorticoid and IL10 signaling shows that each step of the sequence is independently activated. Our results provide the first evidence that macrophages, in addition to a switch from M1 to M2, sequentially and independently transition though three anti-inflammatory pathways in vivo during tissue injury in a regenerating organ. One-Sentence SummaryWe show that macrophages are sequentially activated by three different anti-inflammatory pathways during tissue injury.
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