التفاصيل البيبلوغرافية
| العنوان: |
Ruxolitinib inhibits IFNγ-stimulated Sjögren's salivary gland MSC HLA-DR expression and chemokine-dependent T cell migration. |
| المؤلفون: |
McCoy, Sara S, Parker, Maxwell, Gurevic, Ilya, Das, Rahul, Pennati, Andrea, Galipeau, Jacques |
| المصدر: |
Rheumatology; Oct2022, Vol. 61 Issue 10, p4207-4218, 12p |
| مصطلحات موضوعية: |
SEQUENCE analysis, PROTEIN kinase inhibitors, IMMUNOMODULATORS, INTERFERONS, TREATMENT effectiveness, GENE expression, ENZYME-linked immunosorbent assay, SJOGREN'S syndrome, GENETIC techniques, CHEMOKINES, T cells, SALIVARY gland diseases |
| مستخلص: |
Objectives Sjögren's disease (SjD) is a systemic autoimmune disease characterized by focal lymphocytic infiltrate of salivary glands (SGs) and high SG IFNγ, both of which are associated with elevated lymphoma risk. IFNγ is also biologically relevant to mesenchymal stromal cells (MSCs), a SG resident cell with unique niche regenerative and immunoregulatory capacities. In contrast to the role of IFNγ in SjD, IFNγ promotes an anti-inflammatory MSC phenotype in other diseases. The objective of this study was to define the immunobiology of IFNγ-exposed SG-MSCs with and without the JAK1 & 2 inhibitor, ruxolitinib. Methods SG-MSCs were isolated from SjD and controls human subjects. SG-MSCs were treated with 10 ng/ml IFNγ +/– 1000 nM ruxolitinib. Experimental methods included flow cytometry, RNA-sequencing, chemokine array, ELISA and transwell chemotaxis experiments. Results We found that IFNγ promoted expression of SG-MSC immunomodulatory markers, including HLA-DR, and this expression was inhibited by ruxolitinib. We confirmed the differential expression of CXCL9, CXCL10, CXCL11, CCL2 and CCL7, initially identified with RNA sequencing. SG-MSCs promoted CD4+ T cell chemotaxis when pre-stimulated with IFNγ. Ruxolitinib blocks chemotaxis through inhibition of SG-MSC production of CXCL9, CXCL10 and CXCL11. Conclusions These findings establish that ruxolitinib inhibits IFNγ-induced expression of SG-MSC immunomodulatory markers and chemokines. Ruxolitinib also reverses IFNγ-induced CD4+ T cell chemotaxis, through inhibition of CXCL9, -10 and -11. Because IFNγ is higher in SjD than control SGs, we have identified SG-MSCs as a plausible pathogenic cell type in SjD. We provide proof of concept supporting further study of ruxolitinib to treat SjD. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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