miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis

Abstract

miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In the present study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in lesional skin of psoriasis patients. The expression of miR-146a was about 2-fold higher than that of miR-146b in healthy human skin and it was more strongly induced by stimulation of pro-inflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of psoriasis patients, among which FERMT1 was verified as direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in miR-146a gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a−/− and skin fibroblasts from miR-146a−/− and miR-146b−/− mice stimulated with psoriasis-associated cytokines as compared to wild type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin.

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

“…We have previously observed the downregulation of SERPINB2 in array analysis of keratinocytes transfected with miR‐146a and overexpression of miR‐146a/b in psoriasis patient's lesional skin . Here, we first confirmed the increased SERPINB2 mRNA expression in the lesional and non‐lesional skin of plaque psoriasis patients (Figure A) on the same cohort we previously used for miR‐146a/b expression analysis .…”

“…Psoriatic skin has distinct miRNA expression pattern, among which miR‐146a and miR‐146b (miR‐146a/b) were among highest over‐expressed miRNAs in psoriatic skin . miR‐146a/b differ only by two nucleotides located outside the seed sequence mediating the interaction with mRNA and target similar set of genes . We have previously shown that miR‐146a/b suppress the inflammatory responses of human primary keratinocytes by downregulating members of the NF‐κB pathway, including IL‐1 receptor‐associated kinase 1 (IRAK1) and caspase recruitment domain‐containing protein 10 (CARD10) .…”

“…miR‐146a/b differ only by two nucleotides located outside the seed sequence mediating the interaction with mRNA and target similar set of genes . We have previously shown that miR‐146a/b suppress the inflammatory responses of human primary keratinocytes by downregulating members of the NF‐κB pathway, including IL‐1 receptor‐associated kinase 1 (IRAK1) and caspase recruitment domain‐containing protein 10 (CARD10) . Other studies demonstrate that miR‐146a suppresses the neutrophil chemoattractant capacity of keratinocytes probably by downregulating IL‐8 and chemokine (C‐C motif) ligand 20 (CCL20) and that miR‐146a ‐/‐ mice develop more severe skin inflammation in imiquimod‐induced mouse model of psoriasis …”

The contribution of feedback loops between miRNAs, cytokines and growth factors to the pathogenesis of psoriasis

“…Taken together, it seems that the effect of miR‐146a in the psoriatic inflammation is not simply through the feedback loop we suggested. First, beside miR‐146a, miR‐146b also has modulating role in skin inflammation and proliferation . Second, it was shown recently that miR‐146a is involved in the EFG signalling through directly targeting FERMT1 which regulates cell proliferation through the EGF signalling …”

Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: A prospective cohort study

“…[5][6][7][8] Accumulating evidences have proven that several miRNAs have established their value on the progress of various immune diseases, including RA, systemic lupus erythematosus (SLE), and psoriasis, which uncovered the potential of miRNA as marker for RA progression and prognosis. [9][10][11][12][13][14][15] However, no studies investigate the effect of comprehensive miRNA expression profile on predicting clinical response to TNF inhibitor in RA patients. Thus, in the present study, the aim was to explore the correlation of circulating miRNA expression profile with clinical response to TNF inhibitor in treating active RA patients.…”