Targeted TNF-α Overexpression Drives Salivary Gland Inflammation

Abstract

Chronic inflammation of the salivary glands from pathologic conditions such as Sjögren’s syndrome can result in glandular destruction and hyposalivation. To understand which molecular factors may play a role in clinical cases of salivary gland hypofunction, we developed an aquaporin 5 (AQP5) Cre mouse line to produce genetic recombination predominantly within the acinar cells of the glands. We then bred these mice with the TNF-αglo transgenic line to develop a mouse model with salivary gland–specific overexpression of TNF-α; which replicates conditions seen in sialadenitis, an inflammation of the salivary glands resulting from infection or autoimmune disorders such as Sjögren’s syndrome. The resulting AQP5-Cre/TNF-αglo mice display severe inflammation in the salivary glands with acinar cell atrophy, fibrosis, and dilation of the ducts. AQP5 expression was reduced in the salivary glands, while tight junction integrity appeared to be disrupted. The immune dysregulation in the salivary gland of these mice led to hyposalivation and masticatory dysfunction.

Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

“…In addition, RANTES is produced by many cells types, including T cells and binds to CCR1, CCR3, and CCR5 to mediate chemotaxis of T cells, DCs, eosinophils, NK cells, and mast cells to inflamed tissues (67). Lastly, a mouse model that overexpresses TNFα in salivary tissue specifically develops robust sialadenitis reminiscent of that seen in SS patients (68). Thus, Dcn-induced dysregulation of cytokines and chemokines in the context of pSS likely alters the immune response, including the recruitment of both innate and adaptive cells to sites of inflammation in disease.…”

Insight into Salivary Gland Aquaporins

“…Indeed, TNF-α levels are increased in serum and SG from SS patients [ 63 ]. In addition, targeted TNF-α overexpression drives mouse SG inflammation [ 64 ] and TNF-α treatment of human SG acinar cells induces a significant downregulation of AQP5 expression [ 65 ]. Furthermore, the injection of neutralizing antibodies against TNF-α in non-obese diabetic (NOD) mice reduced SG inflammatory foci and increased AQP5 protein expression [ 66 ].…”

Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids

“…Sialadenitis is one of the main factors of hyposalivation. In this inflammatory condition, it is well known that TNF-α is upregulated and plays some pivotal roles ( Limaye et al, 2019 ; Kang et al, 2011 ; Hong et al, 2019 ). We therefore used our organoid system to analyze the mechanisms of this inflammatory condition as a disease model.…”

“…Sialadenitis is one of the main factors of hyposalivation and is caused by bacterial and viral infections or autoimmune diseases. In these inflammatory conditions, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α, also known as TNF) are upregulated ( Mei et al, 2015 ; Limaye et al, 2019 ). However, the mechanisms of inflammation-induced hyposalivation and its therapeutic targets are not fully understood in the human salivary glands.…”