Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis.
Feiyang MaOlesya PlazyoAllison C BilliLam C TsoiXianying XingRachael WasikowskiMehrnaz Gharaee-KermaniGrace HileYanyun JiangKelly L HarmsEnze XingJoseph KirmaJingyue XiJer-En HsuMrinal K SarkarYutein ChungJeremy Di DomizioMichel GillietNicole L WardEmanual MaverakisEynav KlechevskyJohn J VoorheesJames T ElderJun Hee LeeJ Michelle KahlenbergMatteo PellegriniRobert L ModlinJohann E GudjonssonPublished in: Nature communications (2023)
The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2 + fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2 + fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2 + myeloid cells, CCR7 + LAMP3 + dendritic cells, and CXCR4 expressed on both CD8 + Tc17 cells and keratinocytes, respectively. The SFRP2 + fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.
Keyphrases
- single cell
- dendritic cells
- rna seq
- induced apoptosis
- wound healing
- high throughput
- extracellular matrix
- cell cycle arrest
- rheumatoid arthritis
- regulatory t cells
- oxidative stress
- immune response
- signaling pathway
- atopic dermatitis
- nucleic acid
- systemic lupus erythematosus
- disease activity
- electronic health record
- bone marrow
- ankylosing spondylitis
- big data
- label free
- cell death
- deep learning
- network analysis
- binding protein
- pi k akt
- data analysis