An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury

Abstract

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.

Cytokines IL-1β and IL-10 are required for Müller glia proliferation following light damage in the adult zebrafish retina

“…Similarly, TNF-α is required for Müller glia proliferation in the zebrafish retina, although it is produced in dying retinal neurons (Nelson et al, 2013). Outside the retina, IL-4 suppressed inflammation following zebrafish gill tissue damage (Bottiglione et al, 2020), while IL-10 and IL-4 signaling worked synergistically together to induce synaptogenesis in sensory hair cells and motor neurons in zebrafish (Denans et al, 2022). As numerous signaling events take place during damage and initiation of neuronal regeneration, the dynamic timing and interaction between these cytokines and both neuronal and non-neuronal cells found in the retina may play a critical role in determining the successful regeneration of neurons in the zebrafish retina following injury.…”

Macrophages in tissue repair and regeneration: insights from zebrafish

“…This comprehensive approach better captures the multifaceted nature of macrophages and allows for a more nuanced understanding of their functions. Recent scRNA-seq studies in zebrafish have also supported this notion by revealing the continuous and dynamic activation process of macrophages during heart and neuromast regeneration (Denans et al 2022 ; Hou et al 2020 ; Wei 2023 ).…”

“…More recently, through single-cell RNA sequencing (scRNA-seq) analysis, Tatjana Piotrowski’s group discovered that macrophages undergo three sequential states of anti-inflammatory activation during hair cell regeneration. Although each state is independently activated, they work synergistically to promote regeneration (Denans et al 2022 ).…”