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Updated: Aug 28, 2025
An Ectopic Chemokine Expression Model for Testing Macrophage Recruitment In Vivo
Published on: September 25, 2019
An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in
Nicolas Denans1, Nhung T T Tran2, Madeleine E Swall2
1Stowers Institute for Medical Research, 1000 east 50th street, Kansas City, MO, 64110, USA. ndenans@stowers.org.
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 IL-10 signaling and finally the induction of oxidative phosphorylation by IL-4/Polyamine signaling. Importantly, loss-of-function of glucocorticoid and IL-10 signaling shows that each step of the sequence is independently activated. Lastly, we show that IL-10 and IL-4 signaling act synergistically to promote synaptogenesis between hair cells and efferent neurons during regeneration. Our results show 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.
Insights
Macrophages sequentially adopt anti-inflammatory states, including glucocorticoid, IL-10, and IL-4 signaling, to aid tissue repair. These steps are independent and crucial for regeneration and nerve regrowth.
Area of Science:
- Immunology
- Regenerative Medicine
- Cell Biology
Background:
- Macrophages are vital for tissue repair and regeneration.
- The precise molecular mechanisms and timing of macrophage activation during injury are not fully understood.
Purpose of the Study:
- To elucidate the sequential molecular activation states of macrophages during tissue regeneration.
- To investigate the role of specific anti-inflammatory pathways in macrophage function post-injury.
Main Methods:
- Single-cell analysis of macrophages with high spatio-temporal resolution.
- Live imaging in zebrafish following sensory hair cell death.
- Loss-of-function studies for glucocorticoid and IL-10 signaling pathways.
Main Results:
- Macrophages transition through three distinct anti-inflammatory states: glucocorticoid activation, IL-10 signaling, and IL-4/Polyamine-induced oxidative phosphorylation.
- Each activation step in the sequence is independently regulated.
- IL-10 and IL-4 signaling synergistically promote synaptogenesis between hair cells and neurons.
Conclusions:
- Macrophages exhibit sequential and independent activation of multiple anti-inflammatory pathways during in vivo tissue regeneration.
- This sequential activation is critical for effective tissue repair and functional recovery.
