MiR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome

Qistina Pilson,Siobhan Smith,Conor C Murphy,Caroline A Jefferies,Joan Ní Gabhann-Dromgoole

doi:10.1038/s41598-020-64422-5

Abstract

In primary Sjögren’s syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. Previous investigations have suggested that dysregulated localized and systemic inflammation contributes to the development and pathogenesis of pSS. A miR microarray performed in primary human conjunctival epithelial cells (PECs) demonstrated significant differences in miR expression at the ocular surface between pSS patients and healthy controls. MicroRNA-744-5p (miR-744-5p) was identified as being of particular interest, as its top predicted target is Pellino3 (PELI3), a known negative regulator of inflammation. Validation studies confirmed that miR-744-5p expression is significantly increased in PECs from pSS patients, whilst PELI3 was significantly reduced. We validated the miR-744 binding site in the 3’ untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10. These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino3 expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients.

Highlights

In primary Sjögren’s syndrome the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth
To more fully address the unmet need to understand events occurring at the ocular surface our initial study sought to identify potential differentially expressed miRNA in primary human conjunctival cells (PECs) isolated from s syndrome (SS) patients that may be contributing to ocular surface inflammation
By targeting the ubiquitously expressed phosphatase protein tyrosine phosphatase 1B (PTP1B), miR-744-5p has been shown to play a feedforward role in the type 1 interferon (IFN) pathway by positively enhancing the expression of IFN induced genes (CCL2, CCL5, CXCL10 and IL6)[41]

Summary

Introduction

In primary Sjögren’s syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. We validated the miR-744 binding site in the 3’ untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10 These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino[3] expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients. Increased levels of inflammatory cytokines including interleukin (IL)-6, IL-12, tumour necrosis factor alpha (TNF-α)[7,8,9] and more recently IL-2310 have been observed both locally and systemically and have been shown to play an important role in SS pathogenesis[11,12,13] Autoantibodies such as anti-SSA/Ro and anti-SSB/La are a characteristic hallmark of SS and are thought to contribute to pathogenesis through the formation of immune complexes and associated inflammation. There is strong evidence to suggest that alterations in miR expression contribute to the initiation and progression of pSS, a functional link to pathogenic cytokine production has yet to be established

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Conclusion