Cellular stress leading to epithelial cell dysfunction in Sjögren's syndrome

Cells are highly compartmentalized entities composed of membranous and nonmembranous structures, where organelles such as the endoplasmic reticulum (ER), Golgi apparatus, nucleus, mitochondria, lysosomes, peroxisomes, endosomes, and plasma membrane are organized. The plasma membrane physically and functionally connects the cytoplasm to the extracellular matrix, thereby generating a microenvironment that allows for the development of all the metabolic demands necessary to maintain cellular homeostasis. Salivary gland epithelial cells (SGECs, acinar and ductal) from Sjögren's syndrome (SS) patients undergo structural changes leading to loss of cell polarity and disrupted barrier function, resulting in severe alterations in the architecture of acini and ducts, which are sensed by their subcellular organelles as a condition of stress. The cellular stress response is a defensive mechanism that occurs when a cell loses its homeostasis due to internal or external factors. This response is organized into three sequential components: sensors detect the damage, the signaling cascade transmits the alarm, and effectors execute the adaptive action. One of these adaptive mechanisms is the integrated stress response, which is activated by various stress-inducing factors to adjust protein biosynthetic rates and redirect resources to mitigate stress and restore cellular homeostasis. Another adaptive mechanism is the unfolded protein response, which is activated by the accumulation of unfolded/misfolded proteins to restore ER proteostasis. Altered lysosomes, the Golgi apparatus, and mitochondria can also trigger stress. This review briefly discusses some cellular stress response pathways activated in SGECs, highlighting the perpetuating loop between inflammation and cellular stress in SS.