Interaction between adipocyte lineage cells and mast cells contributes skin inflammation and fibrosis in atopic dermatitis

Summary: Abstract Body: Atopic Dermatitis (AD) is a prevalent chronic inflammatory skin disease, hallmarked by type 2 inflammation. Mast cells (MCs) are pivotal in the initiation of type 2 inflammation and skin itching by secreting proinflammatory cytokines. However, the dermal mechanisms underlying MC recruitment, activation, and their impacts on dermal cells are not fully understood. Dermal white adipose tissue (dWAT), composed of highly plastic and immunogenic adipocyte lineage cells (ALCs), can rapidly expand or regress in response to a variety of stimuli. Yet, the contribution of ALCs to mast cell recruitment and activation during AD development is not well defined. Here, by an in-depth analysis of the MC903-induced AD mouse model, we found that mast cell recruitment to the dWAT layer coincided with the area of adipocyte lipolysis and dermal fibrosis during AD pathogenesis. Single-cell RNAseq revealed that ALCs, particularly preadipocytes (pAds) and adipogenesis regulator (AREG) cells, were the prominent cellular source of key mast cell cytokines/ chemokines, including SCF and CXCL. Using in vivo mouse models and in vitro co-culture systems, we demonstrated that pAds/AREGs effectively induced mast cell migration in a SCF and CXCL-dependent manner. By analyzing MC deficient and adipocyte lineage tracing mice, we found that MC903-mediated mast cell recruitment and degranulation in dWAT led to adipocyte lipolysis and their dedifferentiation into COL1-producing AREGs, thus promoting dermal fibrosis. In summary, our results uncover a previous unrecognized reciprocal interaction between dermal ALCs and MCs, potentially driving skin inflammation and dermal fibrosis in AD. These insights could pave the way for novel therapeutic approaches for atopic dermatitis. Heng Shujun¹, Guo Zhuolin², Li Jie¹, Ling-juan Zhang*¹ 1. School of Pharmaceutical Sciences, The State Key Lab of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China. 2. Department of Dermatology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, Shanghai, China. Cell Communication Networks and Stromal Biology