Loss of ATG5 in KRT14 ⁺ cells leads to accumulated functional impairments of salivary glands via pyroptosis

Abstract

Macroautophagy/autophagy is critically involved in the process of salivary gland (SG) diseases such as xerostomia, which has a serious impact on quality of life. KRT14 + progenitor cells are found to be the main progenitors for maintaining the ductal homeostasis of the submandibular SGs. In this study, we investigated the role of ATG5 in SG KRT14 + cells in mice and humans. Human labial salivary glands (LSG) from primary Sjogren's syndrome (pSS) and non-pSS patients (normal), and submandibular glands (SMG) from Atg5 flox/flox ; Krt14-Cre (cKO) mice were used. ATG5 + KRT14 + and p62 + KRT14 + cells were detected by immunofluorescence staining in LSG. TUNEL, immunofluorescence, immunohistochemistry, and western blot were performed to detect cell death in SMG. Saliva was collected in 12-week-old (12 W) and 32-week-old (32 W) mice, then the concentration of calcium and buffering capacity were detected to analyze the function of SG. We found that LSG from pSS patients showed increased p62 and decreased ATG5 in KRT14 + cells. We further revealed that in 32 W, (1) the function of salivary glands was significantly impaired in cKO mice, (2) cell death increased in cKO mice, but cl-Caspase 3 was not significantly changed, and (3) cleaved gasdermin D increased and was highly expressed in KRT14 + cells of cKO mice. After applying a pyroptosis inhibitor to 32 W mice, the reduced saliva flow rate was rescued. In

The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research

“…Notably, KRT5 and KRT19 are recognized progenitor markers in developing salivary glands 66 . KRT14+ progenitor cells are crucial for maintaining ductal homeostasis in submandibular glands 15, 67 . Our findings also include KRT7, marking differentiated luminal ductal cells, and KRT76, associated with differentiating layers in stratified epithelia.…”

Modes and Mechanisms of Salivary Gland Epithelial Cell Death in Sjogren's Syndrome

“…[62] In addition, significant changes were observed in the specific autophagy substrate sequestosome 1 (SQSTM1, p62) and key participant in autophagosome and autolysosome formation, ATG5, in the lacrimal gland cells of SS patients, with elevated levels of p62 and decreased expression of ATG5. [63][64][65][66] This suggests that inadequate degradation of cellular metabolites resulting from insufficient autophagy in SS could lead to the production of autoantigens. Additionally, autophagy-related proteins (ATG3/5/7) and interleukins (IL-17/21/23), among others, are known to play crucial roles in various signaling pathways, including PI3K/Akt and p38/JNK signaling pathways, involved in signal transduction and cell cycle control in SS (Table 3).…”