Abstract
Sjögren’s Syndrome (SS), a chronic autoimmune disorder affecting multiple organ systems, is characterized by an elevated type I interferon (IFN) response. Activation of Stimulator of Interferon Genes (STING) protein induces type I IFN and in mice, several features of SS, including anti-nuclear antibodies, sialadenitis, and salivary gland dysfunction. Since lung involvement occurs in one-fifth of SS patients, we investigated whether systemic activation of STING also leads to lung inflammation. Lungs from female C57BL/6 mice injected with the STING agonist 5, 6-Dimethylxanthenone-4-acetic acid (DMXAA), were evaluated for acute and chronic inflammatory responses. Within 4h of DMXAA injection, the expression of Ifnb1, Il6, Tnf, Ifng, and Mx1 was significantly upregulated. At 1 and 2 months post-treatment, lungs showed lymphocytic infiltration in the peri-bronchial regions. The lungs from DMXAA treated mice showed an increased expression of multiple chemokines and an increase in lymphatic endothelial cells. Despite STING expression in bronchial epithelium and cells lining the alveolar wall, bone marrow chimeras between STING knockout and wild type mice showed that STING expression in hematopoietic cells was critical for lung inflammation. Our results suggest that activation of the STING pathway might be involved in SS patients with concomitant salivary gland and lung disease.
Highlights
Sjögren’s syndrome (SS) is a systemic autoimmune disorder marked by salivary and lacrimal gland dysfunction [1]
Using mouse strains that spontaneously develop SS-like disease, we showed that repeated toll-like receptor 3 (TLR3) stimulation can exacerbate salivary gland inflammation and dysfunction in NZB/W F1 mice [10] and that signaling through the IFNα/β receptor is required for SS development in B6
Our previous study demonstrated that systemic activation of Stimulator of Interferon Genes (STING) with its agonist Dimethylxanthenone-4-acetic acid (DMXAA) caused a rapid and significant increase in circulating type I IFN and pro-inflammatory cytokines in mice [18]
Summary
Sjögren’s syndrome (SS) is a systemic autoimmune disorder marked by salivary and lacrimal gland dysfunction [1]. We have previously reported that the production of type 1 IFN through activation of toll-like receptor 3 (TLR3) directly inhibits calcium mobilization in salivary gland cells [9]. Female C57BL/6 mice injected with DMXAA, a cell-permeable agonist of murine STING [19], rapidly induced production of type 1 IFN and pro-inflammatory cytokines [18]. The mice subsequently developed anti-nuclear antibodies, salivary gland inflammation, and reduced salivary flow, thereby establishing a role for STING activation in SS pathogenesis. To test the hypothesis that activation of innate immunity through the STING pathway induces lung pathology in SS, mice were injected with DMXAA, and the effects on lung were investigated
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