Spatial transcriptomics uncovers lipid metabolic dysregulation driving immune-stroma crosstalk in Sjögren's Disease.

Abstract

Sjögren's Disease (SjD) is a systemic autoimmune disorder characterised by exocrine gland dysfunction and immune infiltration. However, the spatial cellular architecture and metabolic-immune crosstalk underlying glandular pathology in SjD remain unclear. We performed spatial transcriptomics on SjD salivary glands (SGs) and conducted integrative analyses with single-cell RNA sequencing to delineate disease-specific transcriptomic alterations, followed by validation in an independent cohort. Key findings were verified via immunofluorescence, immunohistochemistry, and function assays on cells. Spatial clustering revealed distinct perturbations in SjD. We identified a pathogenic CCL2^high fibroblast-ACKR1^high endothelial cell axis that co-localised in lymphoid foci and correlated with immune infiltration and disease activity. Chemokine-receptor axes were associated with immune infiltration, with endothelial ACKR1 facilitating inflammatory niche organisation. Compartmentalised immune-stroma niches exhibited upregulated phospholipid, glycerophospholipid and phosphatidylinositol metabolism in lymphoid foci, correlating with B/T-cell activation and interferon responses. Key metabolic regulators (PIK3CD, PIK3CG, PIKFYVE, and PLCG2) were elevated in SjD, associated with CD45⁺ cell abundance in SGs, and exhibited diagnostic potential. Conversely, epithelial cells showed suppressed glycerolipid metabolism and decreased MGLL expression, linked to enhanced antigen presentation. Inhibiting monoacylglycerol lipase (encoded by MGLL) upregulates MHC in A253 cells, while interferon-γ suppresses MGLL expression. Our study elucidates spatially organised metabolic-immune networks in SjD, implicating lipid metabolism in immune activation and epithelial metabolic reprogramming in secretory dysfunction, nominating promising therapeutic targets. National Natural Science Foundation of China (82104484,32301084), Joint funding from schools (colleges) and enterprises in Guangzhou (2025A03J3203, 2024A03J0987), Natural Science Foundation of Guangdong Province (2023A1515012790), Guangdong Provincial Enterprise Joint Fund (2022A1515220003), and Sun Yat-sen University (P02523).