Understanding the Complexity of Sjögren’s Syndrome: Remarkable Progress in Elucidating NF-κB Mechanisms

Sisto, Margherita; Ribatti, Doménico; Lisi, Sabrina

doi:10.3390/jcm9092821

Cited by 9 publications

(7 citation statements)

References 115 publications

(215 reference statements)

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“…TNFAIP3 , HLA-DMA , HLA-DR genes ( HLA-DRB5 and HLA-DRB1 ), CDKN1B (cyclin-dependent kinase inhibitor 1B), IFITM1, NKFB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1), and IRF7 also elevated in labial salivary biopsies ( 53 ). Other small molecules and drugs that target the NFkB pathway in SS are undergoing clinical trials [reviewed in ( 54 )].…”

Section: Resultsmentioning

confidence: 99%

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

et al. 2021

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Sjögren syndrome (SS) is an autoimmune condition that targets the salivary and lacrimal glands, with cardinal clinical signs of dry eye (keratoconjunctivitis sicca, KCS) and dry mouth. The conjunctiva of SS patients is often infiltrated by immune cells that participate in the induction and maintenance of local inflammation. The purpose of this study was to investigate immune-related molecular pathways activated in the conjunctiva of SS patients. Female SS patients (n=7) and controls (n=19) completed a series of oral, ocular surface exams. Symptom severity scores were evaluated using validated questionnaires (OSDI and SANDE). All patients fulfilled the ACR/EULAR criteria for SS and the criteria for KCS. Fluorescein and lissamine green dye staining evaluated tear-break-up time (TBUT), corneal and conjunctival disease, respectively. Impression cytology of the temporal bulbar conjunctiva was performed to collect cells lysed and subjected to gene expression analysis using the NanoString Immunology Panel. 53/594 differentially expressed genes (DEGs) were observed between SS and healthy controls; 49 DEGs were upregulated, and 4 were downregulated (TRAF5, TGFBI, KLRAP1, and CMKLRI). The top 10 DEGs in descending order were BST2, IFITM1, LAMP3, CXCL1, IL19, CFB, LY96, MX1, IL4R, CDKN1A. Twenty pathways had a global significance score greater or equal to 2. Spearman correlations showed that 29/49 upregulated DEGs correlated with either TBUT (inverse) or OSDI or conjunctival staining score (positive correlations). Venn diagrams identified that 26/29 DEGs correlated with TBUT, 5/26 DEGs correlated with OSDI, and 16/26 correlated with conjunctival staining scores. Five upregulated DEGs (CFB, CFI, IL1R1, IL2RG, IL4R) were uniquely negatively correlated with TBUT. These data indicate that the conjunctiva of SS patients exhibits a phenotype of immune activation, although some genes could be inhibitory. Some of the DEGs and pathways overlap with previous DEGs in salivary gland biopsies, but new DEGs were identified, and some of these correlated with symptoms and signs of dry eye. Our results indicate that gene analysis of conjunctiva imprints is a powerful tool to understand the pathogenesis of SS and develop new therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

et al. 2021

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“…Studies have shown that human fetal heart perfusion with anti-SSA can lead to transient heart block, mainly probably because anti-SSA can cross-react with T- and L-type calcium channels and the aforementioned reactions can also cause structural damage to the heart. 27 , 28 It has also been shown that fetal atrial wall and annular echogenicity enhancement on ultrasound during pregnancy is associated with SS. 29 The current study showed that pSS increased the risk of birth defects, suggesting that for pregnant women with SS, obstetric clinics should enhance prenatal consultations and early detection of congenital malformations to reduce birth defects.…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis of the effect of Sjögren′s syndrome on adverse pregnancy outcomes

Geng

Zhang

Huang

et al. 2022

Clinics

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“…Mb-ME also suppressed other inflammatory genes, such as IL-6, MMP9, TNF-α, IL-1β, and COX-2 ( Figure 2 ). In both innate and adaptive immune cells, NF-κB is a central mediator that mediates cell survival, differentiation, and activation of pro-inflammatory genes expression such as cytokines, chemokines, and coagulation factors [ 28 ]. Our results indicate that the nuclear translocation of p50 and p65, two subunits of NF-κB, was suppressed by Mb-ME.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Functions of Methanol Extract from Malus baccata (L.) Borkh. Leaves and Shoots by Targeting the NF-κB Pathway

Song

Chen

Kim

et al. 2022

Plants

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Malus baccata (L.) Borkh. is a widely used medical plant in Asia. Since the anti-inflammatory mechanism of this plant is not fully understood, the aim of this study was to explore the anti-inflammatory function and mechanism of Malus baccata (L.) Borkh. methanol extract (Mb-ME). For in vitro experiments, nitric oxide production assay, PCR, overexpression strategy, immunoblotting, luciferase reporter assay, and immunoprecipitation were employed to explore the molecular mechanism and the target proteins of Mb-ME. For in vivo experiments, an HCl/EtOH-induced gastritis mouse model was used to confirm the anti-inflammatory function. Mb-ME showed a strong ability to inhibit the production of nitric oxide and the expression of inflammatory genes. Mb-ME decreased NF-κB luciferase activity mediated by MyD88 and TRIF. Moreover, Mb-ME blocked the activation of Src, Syk, p85, Akt, p50, p60, IKKα/β, and IκBα in LPS-induced RAW264.7 cells. Overexpression and immunoprecipitation analyses suggested Syk and Src as the target enzymes of Mb-ME. In vitro results showed that Mb-ME could alleviate gastritis and relieve the protein expression of p-Src, p-Syk, and COX-2, as well as the gene expression of COX-2 and TNF-α. In summary, this study implied that Mb-ME performs an anti-inflammatory role by suppressing Syk and Src in the NF-κB signaling pathway, both in vivo and in vitro.

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Understanding the Complexity of Sjögren’s Syndrome: Remarkable Progress in Elucidating NF-κB Mechanisms

Cited by 9 publications

References 115 publications

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

A meta-analysis of the effect of Sjögren′s syndrome on adverse pregnancy outcomes

Anti-Inflammatory Functions of Methanol Extract from Malus baccata (L.) Borkh. Leaves and Shoots by Targeting the NF-κB Pathway

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