MiR-375-3p alleviates the severity of inflammation through targeting YAP1/LEKTI pathway in HaCaT cells

Abstract

Atopic dermatitis (AD) is a relapsing inflammatory skin disease with a complicated pathogenesis. This study aimed to investigate whether miR-375-3p could regulate AD through the Yes-associated protein 1 (YAP1) pathway. In this study, inflammatory response was induced by TNF-α and IFN-γ administration in HaCaT cells. We found that viability and inflammatory factor release, including interleukin-1β (IL-1β) and IL-6, were negatively related to miR-375-3p expression in HaCaT cells. We also found that YAP1 overexpression down-regulated lympho-epithelial Kazal type inhibitor (LEKTI) levels and aggravated viability and inflammation in TNF-α and IFN-γ-treated HaCaT cells. Dual-luciferase reporter assay proved the targeted binding of miR-375-3p and YAP1 3ʹ-UTR. Additionally, the protective effect of miR-375-3p on inflammatory response in TNF-α and IFN-γ-treated HaCaT cells could be impeded by YAP1 overexpression. Collectively, our results suggested that miR-375-3p could modulate HaCaT cell viability and inflammation through the YAP1/LEKTI pathway.

Understanding immunological origins of atopic dermatitis through multi‐omic analysis

“…Reductions in miR-375 have been demonstrated in studies of allergic rhinitis, 25 and increases in miR-375 have been shown to protect against AD-associated inflammation. 6 Based on these findings, we propose a conceptual framework for AD pathogenesis involving Proteobacteria perturbations, miRNA regulation, and perturbations in IL-8/IL-6 (Figure 4). miR-375 has been found to reduce inflammation in allergic conditions through repression of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and downstream effects on IL-6 signaling.…”

“…The RNA features with consistent detection (raw read counts ≥10 in ≥90% of samples) in each category (miRNAs, mRNAs, bacteria) were median‐normalized and mean‐center‐scaled prior to statistical analysis. The following features were selected a priori for comparison between AD and non‐AD groups (based upon their identification in prior studies of atopy): (1) miRNAs—miR‐21‐5p, miR‐375‐3p, and miR‐146b‐5p; (2) mRNAs— Filaggrin (FLG), Serine Peptidase Inhibitor, Kazal Type 5 (SPINK5), and Toll‐like Receptor 4 (TLR4 ); and (3) microbes—alpha diversity (Simpson's index), Actinobacteria, Bacteroidetes, Proteobacteria, and Fusobacteria 5–7,10–12,20 …”

“…miR‐21‐5p, miR‐375‐3p, and miR‐146b‐5p dysregulation has been identified in AD patients 6,7 . For example, miR‐375‐3p has been revealed to regulate cytokine signaling by downregulating tumor necrosis factor‐alpha (TNF‐α) and interferon‐gamma (IFN‐γ) through the Yes‐associated protein 1/lymphoepithelial Kazal‐type‐related inhibitor (YAP1/LEKTI) pathway 6,7 . Additionally, there is evidence that miRNA expression may respond to microbial colonization 8 …”

“…12 Given the potential importance of host-microbe interactions in AD pathogenesis, the correlations between skin and oral microbes, and the ability to measure genetic, cytokine, and miRNA factors by sampling the oral epithelium, the current study harnessed infant saliva samples to interrogate multi-omic networks with potential relevance to AD pathogenesis. [6][7][8][9][11][12][13][14] Although various molecular factors have been implicated in AD pathophysiology, to our knowledge, few studies have employed a multi-omic approach to explore their interactions at the time of initial symptom onset. Such information could enhance our knowledge about the pathophysiologic mechanisms underlying this complex disease, leading to novel approaches for prevention and treatment.…”

MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?

“…For example, massive un-physiological overexpression of miR-375 may “always” result in a growth-suppressive phenotype in vitro in prostate cancer cells or for that matter any cancer cell (e.g., oral cancer). To explore this issue in a more unbiased fashion and shed light on the unsatisfactory conclusions about miR-375’s role in cancer, we selected ten of the most recent publications [ 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ] and ten of the most cited publications [ 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ] that deal with miR-375 and determined the pro- or anti-growth outcomes of its overexpression or inhibition in these studies. Overexpression using a miR-375 mimic produced growth inhibition and/or induction of apoptosis in 16 of the 17 studies, while miR-375 inhibition had either no effect or mild pro-growth effects in 7 of 10 studies.…”