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Single-cell RNA-sequencing of skin immune cells uncover a role for Angptl4-mediated ifi20b expression in monocyte cell fate differentiation during wound healing

ABSTRACT: Angiopoietin-like protein 4 (Angptl4) is a matricellular protein that associates with extracellular matrix proteins, mediating complex cell-cell, and cell-matrix interactions. It has been implicated in various inflammation-associated diseases, including wound healing, but very few reports describe a direct role for Angptl4 in the immune landscape of wound microenvironment. Here, we studied whether Angptl4 regulates the immune response during wound healing. Using single-cell RNA sequencing to examine the temporal changes in the immune cell landscape of excisional wounds from wild type and Angplt4-knockout (Angplt4-/-) mice revealed that Angptl4-/- wounds had a stalled inflammatory phase. Infiltrated neutrophils remained elevated in the Angptl4-/- wounds due to an impaired monocyte to macrophage differentiation needed for clearance. The impaired monocyte differentiation was also validated in wounds using multi-color flow cytometry. Pairwise comparisons of differentially expressed genes from wound-derived and bone-marrow derived macrophages demonstrated few differences, suggesting that Angptl4 has a confined regulome. We identified interferon activated protein 202B (ifi202b) to be consistently upregulated in Angptl4-/- macrophages. . Pathway analysis further confirmed that ifi202b significantly impacted multiple gene networks involved in the cell fate of monocytes and the functions of monocyte-derived macrophages. Taken altogether, we conclude that Angptl4 orchestrates the inflammatory state, innate immune landscape, and healing process in the wound microenvironment via its transcriptional regulation on ifi202b.

ORGANISM(S): Mus musculus

PROVIDER: GSE186986 | GEO | 2022/03/02

REPOSITORIES: GEO

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Project description:Bacterial infections of wounds are associated with poor healing and worse scarring. We sought to identify transcriptomic patterns associated with impaired healing of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) using a rabbit ear wound model. Wounds created on post-operative day (POD) 0 were infected on POD3, within the inflammatory phase of healing. On POD4 the infected wounds were harvested for microarray/transcriptome analysis. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12. On POD4 before antibiotic treatment, both wounds contained elevated transcripts that enriched predominantly into inflammation/infection-response pathways and functions characteristic of infiltrating leukocytes. But there were 5-fold more elevated transcripts in P.a.- than K.p.-infected wounds. Additionally, unique to P.a.-infected wounds, was a minor network of inflammation/infection-response molecules with predicted upstream regulation predominated by type I interferons. Also on POD4, Dnr-transcripts of both wounds were enriched into stress-response pathways such as EIF2 signaling. But there were 8-fold more Dnr-transcripts in P.a.- than K.p.-infected wounds, and many more of them enriched in the function, cell death, suggesting that resident dermal cells of P.a.-infected wounds failed to survive a more destructive P.a. infection. On POD6, following two days of antibiotic treatment, the biofilm-colonized wounds expressed magnitudes fewer inflammation and stress-response transcripts. However, a single regulatory network of P.a.-infected wounds was found to consist of Upr-transcripts enriching immune/infection-response functions predicted to be regulated by type I interferons, which was similar to the network unique to P.a.-infected wounds on POD4. On POD12, genes expressed by K.p.-infected wounds suggesting healing, while for P.a.-infected wounds they suggested stalled healing. The similarities and differences between the wound responses to these infections further define the molecular foundations of healing impaired by infections. Rabbit ear Wounds created on post-operative day (POD) 0 were infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) on POD3 and harvested on POD4 for RNA extraction. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12.

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Single-cell RNA-sequencing of skin immune cells uncover a role for Angptl4-mediated ifi20b expression in monocyte cell fate differentiation during wound healing

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