H3K18 Lactylation in Salivary Gland Epithelial Cells Regulates Autophagy and Is Associated With the Progression of Sjögren Syndrome

Abstract

Abnormal signal transduction within glandular epithelial cells is a pathological feature of advanced Sjögren syndrome (SS). Preliminary investigations have demonstrated that the progression of SS is marked by a substantial accumulation of metabolic byproducts, notably lactate, in the salivary glands. This study corroborated the accumulation of lactate within the salivary glands by analyzing peripheral blood and lip gland tissue samples from patients with SS in addition to constructing an experimental Sjögren syndrome mouse model. Lactate exacerbates the severity of xerostomia and the extent of immune cell infiltration in the salivary glands. Moreover, the ability of lactate transport proteins, including MCT1 and SLC5A12, to regulate the transport of lactate in and out of cells, thereby facilitating the process of histone lactylation, was confirmed via experimental methodologies such as western blotting. Preliminary findings derived from chromatin immunoprecipitation sequencing and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that H3K18la directly influences the downstream autophagy signaling pathway. Subsequent validation using western blot analysis revealed associations between various key regulatory and autophagy-related proteins and the lactate microenvironment. Moreover, the relationship between apoptosis and autophagy levels was elucidated through annexin/propidium iodide staining. Flow cytometry confirmed that lactate levels regulate the level of the autophagy marker protein LC3B-II. Transmission electron microscopy confirmed an increase in the number of autophagosomes in a high-lactate environment. These findings indicate that lactate exacerbates SS symptoms and the degree of immune cell infiltration and that H3K18la directly regulates the autophagy signaling pathway within glandular epithelial cells, thus contributing to the progression of SS.