Role of tissue homeostasis in Sjogren's disease

About This Grant

PROJECT SUMMARY Sjögren’s disease (SjD) is a chronic autoimmune disease characterized by immune cell infiltration of the exocrine glands, which mainly comprise the salivary glands (SGs) and lacrimal glands (LGs). An accumulating number of studies show a significant association between the prevalence of autoimmune diseases and abnormal lipid metabolic conditions and wherein changes in lipid metabolism contribute to disease development. However, how abnormal lipid/cholesterol metabolic conditions contribute to SjD development is unclear. Currently, most patients are diagnosed at later stages of the disease. Therefore, understanding the earlier events in disease development prior to clinical manifestations is essential to identify novel targets for therapeutics and new diagnostic tools for early detection of SjD in at-risk populations, such as those with changes in lipid/cholesterol metabolism. Our preliminary studies found that the expression of INSIG1 and INSIG2, negative regulators of cholesterol synthesis, was significantly downregulated in SjD patients, thus resulting in high cholesterol levels. In agreement with these findings, we found that mice with a deficiency for Insig1/2 in the SGs (Insig1/2 cKO mice) exhibited SjD-like phenotypes with complete penetrance. Interestingly, our preliminary study shows that defects in exocytosis, a system for salivary protein secretion, and elevation of oxidative stress are detectable prior to SjD-like phenotypes (acinar cell death/hyposalivation and autoantibodies detection/inflammation) appear in Insig1/2 cKO mice. Therefore, this study aims to determine how cholesterol metabolic abnormalities in the SGs lead to exocytosis dysregulation and acinar cell death (Aim 1), and how cholesterol metabolic aberrations induce oxidative stress-inflammation (Aim 2) in SjD. In Aim 1, we will track exocytosis under a live-imaging system using newly developed Gate16-eGFP reporter mice, allowing us to visualize the dysregulated exocytosis process in Insig1/2 cKO mice. In addition, we will identify the underlying mechanism that leads to dysregulated exocytosis by genomics and proteomics approaches. In Aim 2, we will determine how oxidated cholesterol (a.k.a. oxycholesterol), a harmful cholesterol linked to inflammation, is induced and contributes to SjD pathogenesis and characterize the immune response to defects in local tissue homeostasis. A detailed understanding of the mechanism(s) by which cholesterol metabolism links to exocytosis and inflammation and how these cascades and loops contribute to SjD will provide new knowledge of the pathogenesis of SjD, advancing our understanding of autoimmune diseases.