Interleukin-17 Impairs Salivary Tight Junction Integrity in Sjögren’s Syndrome

Abstract

Sjögren's syndrome (SS) is an inflammatory autoimmune disease that causes secretory dysfunction of the salivary glands. It has been reported that proinflammatory cytokine interleukin-17 (IL-17) was elevated and tight junction (TJ) integrity disrupted in minor salivary glands from SS patients. However, whether the elevated IL-17 in SS affects TJ integrity and thereby alters the function of salivary gland is unknown. Here, by using nonobese diabetic (NOD) mice as SS model, we found that the stimulated salivary flow rate was significantly decreased in NOD mice. Lymphocyte infiltration was mainly observed in submandibular glands (SMGs), but not parotid glands (PGs), of NOD mice. IL-17 was significantly increased and mainly located in lymphocytic-infiltrating regions in SMGs but not detectable in PGs of NOD mice. Meanwhile, the epithelial barrier function was disrupted, as evidenced by an increased paracellular tracer clearance and an enlarged acinar TJ width in SMGs of NOD mice. Furthermore, claudin-1 and -3 were elevated especially at the basolateral membranes, whereas claudin-4, occludin, and zonula occludens-1 (ZO-1) were reduced in SMGs of NOD mice. Moreover, occludin and ZO-1 were dispersed into cytoplasm in SMGs of NOD mice. However, no change in the expression and distribution of TJ proteins was found in PGs. In vitro, IL-17 significantly decreased the levels and apical staining of claudin-4 and ZO-1 proteins in the cultured SMG tissues, as well as claudin-1, occludin, and ZO-1 in PG tissues. Moreover, IL-17 activated the phosphorylation of IκBα and p65 in SMG cells, whereas pretreatment with NF-κB inhibitor pyrrolidine dithiocarbamate suppressed the IL-17-induced downregulation of claudin-4 and ZO-1 in SMG tissues. Taken together, these findings indicate that IL-17 derived from infiltrating lymphocyte impairs the integrity of TJ barrier through NF-κB signaling pathway, and thus might contribute to salivary gland dysfunction in SS.

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

“…The expression and organization of TJ proteins are altered during several pathological processes of xerostomia (Ewert et al , 2010; Mellas et al , 2015; Ding et al , 2017; Cong et al , 2018; Zhang et al , 2019). In salivary glands of SS patients and NOD mice, the integrity of TJs is disrupted, including elevated Cldn1 and Cldn3 expression as well as reduced Cldn4, Ocln, and ZO‐1 expression (Zhang et al , 2016). ZO‐1 is also observed to be decreased in post‐irradiated human SMG (Nam et al , 2016).…”

“…In hyposecretory SMG, acinar TJ width is decreased, while the expression of ZO‐1, Cldn3, and Cldn11 are reduced (Cong et al , 2012; Yang et al , 2017). Additionally, both epithelial and endothelial TJs are disrupted in salivary glands of patients with Sjögren's syndrome (SS) as well as model mice, contributing to salivary hyposecretion (Zhang et al , 2016; Cong et al , 2018). Moreover, TJs are reportedly damaged in other diabetes complications (Jiang et al , 2019; Bu et al , 2020).…”

Heterogeneity of tissue IL-17 and tight junction proteins expression demonstrated in patients with autoimmune thyroid diseases

“…[ 33 ] Recently, Rebuffat et al [ 31 ] showed that Tj protein – ZO-1, claudin-1, and JAM-A protein organization and expression as well as localization in the thyroid tissue of patients suffering from AITD are modified by proinflammatory cytokine IL-1β thus affecting thyroid epithelium integrity. Zhang et al [ 34 ] explored the signaling pathway that links IL-17 with Tj in salivary gland cell culture and postulated that IL-17 could directly modulate Tj protein expression and distribution through the NF-κB signaling pathway. To evaluate whether there is a relationship between IL-17 and Tj disruption, we did correlation analysis between the levels of IL-17 and Tj proteins expression in AITD patients, but no significant association with IL-17A was found.…”

Mesenchymal stem cells inhibited the differentiation of MDSCs via COX2/PGE2 in experimental sialadenitis

“…Sjögren's syndrome (SS) as a chronic systemic autoimmune disease is characterized by mononuclear infiltration in the exocrine glands, which results in salivary and lacrimal gland functional impairment [1]. Immunocomplex deposition caused by B cell hyperactivity implies the underlying pathogenesis [2], and other immune cell abnormal activations also display an important pathogenic role in SS pathological processes [3,4]. Due to the complex syndrome of SS, clarifying the pathogenic mechanisms and improving the therapeutic strategy still are major challenges.…”