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Posted On: 05/05/2020 3:54:47 AM
Post# of 148934
Is this one more disease (Rantes included) to be cured by Leron ?
https://www.nature.com/articles/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.
Results
Altered miRNA expression at the ocular surface in pSS patients
Previous investigations have focused on salivary gland or peripheral blood mononuclear cells in human and mice studies of pSS. More recent studies have examined the levels of inflammatory cytokines and chemokines in ocular washes from pSS patients34,35,36,37. Consistent with these investigations we observed significantly enhanced production of interferon gamma (IFNγ), IL-2, IL-4, IL-5, IL-10, IL-12, IL-13 and TNFα (Supplemental Fig. 1). 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 SS patients that may be contributing to ocular surface inflammation. A total of 20 patients with pSS who fulfilled the AECG criteria were included in this study. Eleven healthy volunteers constituted the control group. Patient demographic data and results of ocular surface parameters are presented in Table 1. The expression of >2000 miRNAs in samples derived from 5 pSS patients and 5 healthy controls by impression cytology (IC) were investigated by Ocean Ridge Bioscience using ORB MirBASE Version 19 MicroRNA Microarray. This study revealed differential expression profiles of miRNA in patients with pSS as compared with healthy controls (Fig. 1A). Among these miR-744-5p was of interest due to previous reports showing altered expression in the autoimmune condition SLE38,39 as well as potentially functioning as a regulator of transforming growth factor beta 1 (TGF-β1) synthesis40. Additionally, 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. Significantly increased expression of miR-744-5p (P ≤ 0.02) was observed in a larger cohort of PECs derived from 19 patients with pSS and 11 healthy controls (Fig. 1B). Comparing multiple miRNA target prediction programs including, miRDB, miRWalk and DIANA, we identified Pellino 3 (PELI3) as a putative target of miR-744-5p and demonstrated significantly reduced (P ≤ 0.01) expression of the gene in PECs from pSS patients compared to healthy controls (Fig. 1C).
https://www.nature.com/articles/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.
Results
Altered miRNA expression at the ocular surface in pSS patients
Previous investigations have focused on salivary gland or peripheral blood mononuclear cells in human and mice studies of pSS. More recent studies have examined the levels of inflammatory cytokines and chemokines in ocular washes from pSS patients34,35,36,37. Consistent with these investigations we observed significantly enhanced production of interferon gamma (IFNγ), IL-2, IL-4, IL-5, IL-10, IL-12, IL-13 and TNFα (Supplemental Fig. 1). 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 SS patients that may be contributing to ocular surface inflammation. A total of 20 patients with pSS who fulfilled the AECG criteria were included in this study. Eleven healthy volunteers constituted the control group. Patient demographic data and results of ocular surface parameters are presented in Table 1. The expression of >2000 miRNAs in samples derived from 5 pSS patients and 5 healthy controls by impression cytology (IC) were investigated by Ocean Ridge Bioscience using ORB MirBASE Version 19 MicroRNA Microarray. This study revealed differential expression profiles of miRNA in patients with pSS as compared with healthy controls (Fig. 1A). Among these miR-744-5p was of interest due to previous reports showing altered expression in the autoimmune condition SLE38,39 as well as potentially functioning as a regulator of transforming growth factor beta 1 (TGF-β1) synthesis40. Additionally, 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. Significantly increased expression of miR-744-5p (P ≤ 0.02) was observed in a larger cohort of PECs derived from 19 patients with pSS and 11 healthy controls (Fig. 1B). Comparing multiple miRNA target prediction programs including, miRDB, miRWalk and DIANA, we identified Pellino 3 (PELI3) as a putative target of miR-744-5p and demonstrated significantly reduced (P ≤ 0.01) expression of the gene in PECs from pSS patients compared to healthy controls (Fig. 1C).
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