Multi-Omics Analysis Identifies Fibroblast-Associated Stromal–Immune Networks Linked to Pregnancy-Associated Attenuation of Imiquimod-Induced Psoriatic Dermatitis

Background: Psoriasis is a chronic, immune-mediated inflammatory skin disorder that frequently exhibits spontaneous clinical remission during pregnancy. However, the underlying cell-type-specific transcriptomic alterations—particularly the involvement of dermal fibroblasts and hormone receptor signaling—remain poorly understood. Methods: We established an imiquimod (IMQ)-induced psoriasis-like dermatitis model in BALB/c mice comparing pregnant and non-pregnant cohorts. Multi-omics profiling combing bulk and single-cell RNA sequencing was integrated with computational intercellular communication and trajectory analysis. In vitro hormone-stimulation assays with ELISA quantification and in situ multiplex immunofluorescence were performed for experimental evaluation. Results: Compared with non-pregnant IMQ-treated mice, pregnant mice exhibited reduced psoriasis area and severity index scores and diminished epidermal thickening. Bulk RNA sequencing revealed downregulated Th1/Th17 inflammatory transcripts and upregulated hormone-associated genes (e.g., Pgr, Esr1, Ghr). Single-cell RNA sequencing identified 11 distinct cell types, with fibroblasts displaying distinct hormone receptor profiles and functional heterogeneity. Fibroblasts displayed transcripts encoding both anti-inflammatory factors (e.g., Tgfb2, Gas6, Grn) and pro-inflammatory factors (e.g., Fgf7, Mif). Keratinocytes exhibited an anti-inflammatory transcriptional phenotype with attenuated proliferation signatures. Monocytes/macrophages shifted toward M2-like transcriptional signatures and displayed computationally predicted communication with fibroblasts via candidate pathways including GRN and Gas6. Experimentally, primary mouse dermal fibroblasts stimulated with estradiol, progesterone, and growth hormone in vitro significantly increased secretion of PGRN. Gas6 secretion was significantly augmented by estradiol and growth hormone, whereas progesterone induced a modest elevation with borderline significance (p = 0.060). In contrast, TGF-β2 protein remained undetectable in culture supernatants. Furthermore, multiplex immunofluorescence demonstrated significantly increased expression of the Gas6 receptor MerTK on dermal macrophages in the IMQ + pregnancy group. Conclusions: Pregnancy-induced hormonal fluctuations may be associated with the amelioration of IMQ-induced psoriatic dermatitis, which correlates with a fibroblast-involved immunoregulatory network. These findings highlight the association of stromal-immune crosstalk in disease remission and suggest the GRN and Gas6 pathways as candidate pathways for future functional validation.