Tear miRNAs Identified in a Murine Model of Sjögren’s Syndrome as Potential Diagnostic Biomarkers and Indicators of Disease Mechanism

Abstract

ObjectiveThe tear miRNAome of the male NOD mouse, a model of ocular symptoms of Sjögren’s syndrome (SS), was analyzed to identify unique miRNAs.MethodsMale NOD mice, aged 12-14 weeks, were used to identify tear miRNAs associated with development of autoimmune dacryoadenitis. Age- and sex-matched male BALB/c mice served as healthy controls while age-matched female NOD mice that do not develop the autoimmune dacryoadenitis characteristic of SS were used as additional controls. Total RNA was isolated from stimulated tears pooled from 5 mice per sample and tear miRNAs were sequenced and analyzed. Putative miRNA hits were validated in additional mouse cohorts as well as in tears of SS patients versus patients with another form of dry eye disease, meibomian gland disease (MGD) using qRT-PCR. The pathways influenced by the validated hits were identified using Ingenuity Pathway Analysis.ResultsIn comparison to tears from both healthy (male BALB/c) and additional control (female NOD) mice, initial analy1sis identified 7 upregulated and 7 downregulated miRNAs in male NOD mouse tears. Of these, 8 were validated by RT-qPCR in tears from additional mouse cohorts. miRNAs previously implicated in SS pathology included mmu-miR-146a/b-5p, which were significantly downregulated, as well as mmu-miR-150-5p and mmu-miR-181a-5p, which were upregulated in male NOD mouse tears. All other validated hits including the upregulated miR-181b-5p and mmu-miR-203-3p, as well as the downregulated mmu-miR-322-5p and mmu-miR-503-5p, represent novel putative indicators of autoimmune dacryoadenitis in SS. When compared to tears from patients with MGD, miRNAs hsa-miR-203a-3p, hsa-miR-181a-5p and hsa-miR-181b-5p were also significantly increased in tears of SS patients.ConclusionsA panel of differentially expressed miRNAs were identified in tears of male NOD mice, with some preliminary validation in SS patients, including some never previously linked to SS. These may have potential utility as indicators of ocular symptoms of SS; evaluation of the pathways influenced by these dysregulated miRNAs may also provide further insights into SS pathogenesis.

Lactobacillus acidophilus and propionate attenuate Sjögren’s syndrome by modulating the STIM1-STING signaling pathway

“…Sjögren’s syndrome (SS), first described in 1933 [ 1 ], is an autoimmune disease mediated by the infiltration of lymphocytes into the exocrine glands, including the salivary and lacrimal glands [ 2 , 3 ]. Lymphocyte infiltration leads to destruction of glandular tissue and dysfunctional glandular secretion, followed by dry eyes and mouth [ 4 , 5 ].…”

Study on the mechanism of miRNAs on liver injury in the condition of Protoscocephalus alveolarus transhepatic portal vein infection

“…Wei Cong et al suggested that mmu‐miR‐30e‐3p were also differentially expressed in liver tissue from rats with acute Toxoplasma gondii infection, 26 however, mmu‐miR‐30e‐3p targeting IL‐1rn regulates the inflammatory response caused by parasitic infections and no studies have been reported. Hu et al found that miR‐203‐3p may bind to vascular endothelial growth factor A (Vegfa) and participate in snhg8‐mediated apoptosis and angiogenesis in AML cells 27 . Moreover, mmu‐miR‐203‐3p was identified as a potential diagnostic biomarker and indicator of Sjögren's syndrome 28 .…”

Role of microRNAs in Immune Regulation with Translational and Clinical Applications

“…miR-17-92 (rs4284505) [113], miR-146a [114], miR-365a-3p [115], miR-4689 [116] miR-21 [117], miR-124-3p, miR-146, miR-320b, miR-377-3p [118,119] miR-181a, miR-223 [120], miR-485-5p [121] miR-7 [122], miR-30a [123], miR-181d-5p [124], miR-590-3p [125] Antiphospholipid syndrome miR-326, miR-483-3p [126] miR-19b-3p, miR-20a-5p [127] miR-146a-5p [128] Systemic sclerosis, scleroderma miR-21 [129], miR-126 [130], miR-155-5p [131] miR-21 [132], miR-27a [133], miR-29a, miR-138 [134] miR-21-5p, miR-29a-3p, miR-143, miR-155 [135], miR-181b-5p, miR-210-3p, miR-223-3p [136] miR-27a [137], miR-214 [138] Sjögren's syndrome miR-181d-5p [139], miR-223-3p [140] miR-30 [141], miR-181b-5p, miR-322-5p, miR-424-5p, miR-503-5p [142], miR-513c-3p [143], miR-1290, let-7b-5p [144] miR-92a [145] miR-16, miR-125b [146], miR-142, miR-223 [147], let-7 [148] Autoimmune vasculitis miR-424-5p [149] miR-24-3p [150], miR-30a-5p, miR-33, miR-34 [151], miR-99a-5p, miR-106b-5p, miR-133a [152], miR-146a-5p [149], miR-148b-3p, miR-155-5p, miR-182-5p…”

“…Combined evaluation of exosome-derived miR-1290 and let-7b-5p in mouth-rinse samples distinguished patients with Sjögren's syndrome from healthy volunteers with 91.7% sensitivity and 83.3% specificity [144]. According to results obtained from a murine model of Sjögren's syndrome, miR-181b-5p, miR-322-5p and miR-503-5p may be applied as novel biomarkers of autoimmune dacryoadenitis [142]. In minor salivary gland tissue samples of patients with primary Sjögren's syndrome, the expression level of miR-92a inversely correlated with disease severity [145].…”