A senescent subpopulation of fibroblasts induce inflammation in psoriasis through APOE

Summary: Abstract Body: Fibroblasts play a critical role in various inflammatory skin diseases, including vitiligo, atopic dermatitis, and psoriasis; however, the precise mechanisms are not fully understood. Single-cell RNA-sequencing analysis for patients with inflammatory skin diseases and healthy individuals have revealed an increased subpopulation of fibroblasts exhibiting senescent phenotype. This group of fibroblasts demonstrate pro-inflammatory characteristics and show elevated expression of APOE. We hypothesized that APOE+ senescent fibroblasts are a key subpopulation participating in inflammatory skin diseases. In the present study, we found that the number of APOE+ fibroblasts was increased in lesional skin of psoriasis patients as shown by immunofluorescence. We also found that overexpression of APOE in fibroblasts resulted in heightened inflammation, lipid metabolism disorders, and cellular senescence. Mice with fibroblast-specific deletion of APOE exhibited attenuated cutaneous inflammation in imiquimod (IMQ) models, which suggested that APOE+ fibroblasts amplified inflammatory responses. Based on single-cell RNA sequencing and flow cytometry, we found that APOE+ fibroblasts exacerbate psoriasis-like inflammation by recruiting neutrophils through overproduction of CXCL1 and CXCL2. Moreover, lipidomics combined with transcriptomic analysis showed that, overexpression of APOE in fibroblasts leads to a significant increase in prostaglandin E2 (PGE2) levels. And the upregulation of CXCL1 and CXCL2 induced by APOE was reversed by inhibiting the PGE2/EP4/AKT/NF-κB pathway. Moreover, application of ABT-263 eliminated the APOE+ fibroblasts-induced inflammation, which represents a potential strategy for control of skin inflammation. Overall, our study reveals that APOE+ fibroblasts exhibit pro-inflammatory function with senescent phenotype and promote skin inflammation of psoriasis. Targeting APOE+ fibroblasts might be a promising strategy for alleviating skin inflammation. Qiaochu Jiang¹, Ronghui Zhu⁴, Rui He², Xu Yao³, Wei Li¹ 1. Huashan Hospital Fudan University, Shanghai, China. 2. Fudan University School of Basic Medical Sciences, Shanghai, China. 3. Chinese Academy of Medical Sciences, Nanjing, China. 4. Wuhan No. 1 Hospital, Wuhan, China. Cell Communication Networks and Stromal Biology