Apoptosis recognition receptors regulate skin tissue repair in mice.
Olivia JustynskiKate BridgesWill KrauseMaria Fernanda ForniQuan M PhanTeresa Sandoval-SchaeferKristyn CarterDiane E KingHenry C HsiaMichael I GazesSteven D VyceRyan R DriskellKathryn Miller-JensenValerie HorsleyPublished in: eLife (2023)
Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1 + macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for efferocytosis pathway genes and display altered efferocytosis signaling via the receptor Axl and its ligand Gas6 . During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.
Keyphrases
- cell death
- cell cycle arrest
- single cell
- oxidative stress
- wound healing
- induced apoptosis
- dendritic cells
- endoplasmic reticulum stress
- rna seq
- anti inflammatory
- tyrosine kinase
- immune response
- genome wide
- computed tomography
- machine learning
- signaling pathway
- magnetic resonance
- inflammatory response
- high fat diet induced
- type diabetes
- patient safety
- transcription factor
- gene expression
- mesenchymal stem cells
- extracellular matrix
- big data
- toll like receptor
- deep learning
- case control
- contrast enhanced
- insulin resistance
- sensitive detection
- genome wide analysis