Lipid Metabolism: An Emerging Player in Sjögren’s Syndrome

Figures

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  Fig. 1. Effects of lipid metabolism on exocrine gland inflammation in SS. Compared to healthy individuals, SS patients exhibit marked dyslipidemia, characterized by significantly reduced levels of HDL cholesterol and elevated levels of TC, LDL cholesterol, and TGs. Dyslipidemia induces lipoprotein lipase (LPL) activity, which breaks down TGs into fatty acids, leading to lipid deposition in target glands. Abnormal metabolism of unsaturated or saturated fatty acids results in mitochondrial dysfunction, endoplasmic reticulum stress, and increased production of reactive oxygen species (ROS), which can trigger apoptosis in salivary and lacrimal gland cells. This process leads to the breakdown of α-fodrin, with mononuclear macrophages recognizing and migrating toward the affected glands. Additionally, hyperlipidemia activates dendritic cells through the TLR-4 pathway, stimulating IL-27 production and promoting further immune cell recruitment to the affected glands. Lipid deposition in the salivary glands induces IL-6 production by salivary epithelial cells, driving B cell maturation and promoting the survival of plasma cells. This, in turn, exacerbates the inflammatory environment, amplifying…

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  Fig. 2. Effects of lipid metabolism disorders on T cells in SS. In T cells, fatty acids and cholesterol are essential for their proliferation, differentiation, and morphogenesis, supporting critical processes such as membrane synthesis, energy production, and TCR signal transduction. The proliferation, maturation, and activation of T cells contribute to acinar damage in the exocrine glands. Notably, the synthesis and accumulation of FAs promote the differentiation of proinflammatory Th17 cells, which play a pivotal role in the pathogenesis of SS development

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  Fig. 3. Effects of lipid metabolism disorders on B cells in SS. In B cells, lipids stimulate the production of IL-6 by salivary gland epithelial cells, which, in turn, promotes the maturation of B cells into antibody-secreting cells and supports the survival and maintenance of plasma cells in SS

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  Fig. 4. Effects of lipid metabolism disorders on macrophages in SS. In macrophages, lipids are recognized by TLRs as pathogen-associated molecular patterns and play a crucial role in the initiation and perpetuation of chronic inflammation in SS. Dyslipidemia induces metabolic reprogramming in macrophages, which can lead to the generation of ROS, further amplifying the inflammatory process

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  Fig. 5. Effects of lipid metabolism disorders on DC cells in SS. Lipids act as second messengers and effectors during DC differentiation and regulate their necessary migration by inducing IL-1 production from vascular endothelial cells for the progression of SS

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  Fig. 6. Regulating lipid metabolism could be a therapeutic strategy for treating SS. The following strategies can potentially target the lipid metabolism to effectively treat SS: (1) dietary control: calorie restriction can improve pSS status by reducing immune activity in glandular tissues. Oral supplementation with ω−6 and ω−3 fatty acids can improve dry eye symptoms; (2) lipid-modifying therapies: statins, fibrate, and HCQ can improve blood lipid abnormalities in SS patients and exert anti-inflammatory effects. Statins, HUWE1 inhibitors, and ketoconazole can inhibit the proliferation and activation of CD4+ T cells by affecting cholesterol metabolism; (3) drugs targeting lipid metabolism: LPAR1/LPAR3 antagonist Ki16425 restores tear and saliva secretion, reducing IL-17 levels in serum and lacrimal glands. Myriocin reduces IFN-γ and Th1 cells and increases the expression of AQP5 and NKCC1, promoting water movement and salivary gland function recovery; (4) RvD1 treatment: RvD1 reduces the secretion of various inflammatory factors, enhances macrophage phagocytosis of apoptotic cells, reduces conjunctival goblet cell secretion stimulated by leukotriene, blocks TNF-α-mediated caspase-3…