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

Vaher, Helen; Kivihall, Anet; Runnel, Toomas; Raam, Liisi; Prans, Ele; Maslovskaja, Julia; Abram, Kristi; Kaldvee, Bret; Mrowietz, Ulrich; Weidinger, Stephan; Kingo, Külli; Rebane, Ana

doi:10.1111/exd.14049

Cited by 24 publications

(23 citation statements)

References 63 publications

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“…SERPINB2 is highly expressed during inflammation, infection, and tissue damage, indicating its immune features [24,25]. A previous study revealed that SERPINB2 and miR-146a-5p are highly expressed in psoriatic skin and SERPINB2 was suppressed by miR-146a-5p [26]. Our study revealed that SERPINB2 inhibition could reduce the differentiation of Th2 cells, whereas its overexpression exhibited reversed effects.…”

Section: Discussionsupporting

confidence: 49%

HMSC-Derived Exosome Inhibited Th2 Cell Differentiation via Regulating miR-146a-5p/SERPINB2 Pathway

Zhou

Lü

2021

Journal of Immunology Research

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Background. Allergic rhinitis (AR) is a global disease without specific treatment. Human mesenchymal stem cell- (HMSC-) derived exosomes (HMSC-exos) have been implicated for the amelioration of allergic inflammation by delivering miR-146a-5p in a mouse asthma model. However, the antiallergic activity and the underlying mechanism of HMSC-exos in AR remain unclear. The present study aimed to investigate the role of HMSC-exos in the pathogenesis of AR. Materials and Methods. Blood specimens were collected from AR patients and healthy donators for investigation. HMSC and CD4+ T cells were used in the present study. Flow cytometry was used to characterize the population of Type 1 helper T (Th1) and Th2 cells. Specific siRNA and overexpressed plasmids were designed to silence or overexpress the expressions of miR-146a-5p and SERPINB2. Luciferase reporter assay was adopted to explore the binding site of miR-146a-5p and SERPINB2. Quantitative real-time PCR and immunoblots were performed to estimate the expression of target genes. Results. The population of Th2 cells was significantly elevated in AR patients as compared with that in healthy donators. HMSC-exos could decrease the expression of SERPINB2 and the differentiation of Th2 cells. miR-146a-5p in HMSC-exos exhibited consistent effects and lowered the expression of SERPINB2 by binding on its 3 ′ UTR region. Moreover, the differentiation of Th2 cells was promoted by SERPINB2 that could be reversed by HMSC-exos. Additionally, the miR-146a-5p expression was negatively associated with the SERPINB2 expression in the serum of AR patients. Conclusion. HMSC-exos could inhibit the differentiation of Th2 cells via the regulation of the miR-146a-5p/SERPINB2 pathway. miR-146a-5p and SERPINB2 could be applied as potential targets for AR treatment.

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Section: Discussionsupporting

confidence: 49%

HMSC-Derived Exosome Inhibited Th2 Cell Differentiation via Regulating miR-146a-5p/SERPINB2 Pathway

Zhou

Lü

2021

Journal of Immunology Research

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“…The miR‐146 family consists of miR‐146a and miR‐146b (miR‐146a/b) that differ by only two nucleotides in their 3′ region, which is considered less significant for their interaction with mRNA targets. As such, miR‐146a/b has been reported to have a similar set of target genes 22–24 . Previous studies have demonstrated that multiple components, including interleukin‐1 receptor‐associated kinase 1 (IRAK1) and caspase recruitment domain 10 (CARD10), from the NF‐κB pathway are directly targeted by miR‐146a/b 23,25 .…”

Section: Introductionmentioning

confidence: 99%

“…As such, miR-146a/b has been reported to have a similar set of target genes. [22][23][24] Previous studies have demonstrated that multiple components, including interleukin-1 receptor-associated kinase 1 (IRAK1) and caspase recruitment domain 10 (CARD10), from the NF-κB pathway are directly targeted by miR-146a/b. 23,25 Accordingly, overexpression of miR-146a/b has been shown to suppress endogenous levels of IRAK1 and CARD10 and of NF-κB-inducible chemokines IL-8 and chemokine (C-X-C motif) ligand 1 (CXCL1) in multiple cell types, including human bronchial epithelial cells (HBECs).…”

Section: Introductionmentioning

confidence: 99%

Dual role of the miR‐146 family in rhinovirus‐induced airway inflammation and allergic asthma exacerbation

Laanesoo

Urgard

Periyasamy

et al. 2021

Clinical & Translational Med

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Rhinovirus (RV) infections are associated with asthma exacerbations. MicroRNA‐146a and microRNA‐146b (miR‐146a/b) are anti‐inflammatory miRNAs that suppress signaling through the nuclear factor kappa B (NF‐κB) pathway and inhibit pro‐inflammatory chemokine production in primary human bronchial epithelial cells (HBECs). In the current study, we aimed to explore whether miR‐146a/b could regulate cellular responses to RVs in HBECs and airways during RV‐induced asthma exacerbation. We demonstrated that expression of miR‐146a/b and pro‐inflammatory chemokines was increased in HBECs and mouse airways during RV infection. However, transfection with cell‐penetrating peptide (CPP)‐miR‐146a nanocomplexes before infection with RV significantly reduced the expression of the pro‐inflammatory chemokines CCL5, IL‐8 and CXCL1, increased interferon‐λ production, and attenuated infection with the green fluorescent protein (GFP)‐expressing RV‐A16 in HBECs. Concordantly, compared to wild‐type ( wt ) mice, Mir146a/b −/− mice exhibited more severe airway neutrophilia and increased T helper (Th)1 and Th17 cell infiltration in response to RV‐A1b infection and a stronger Th17 response with a less prominent Th2 response in house dust mite extract (HDM)‐induced allergic airway inflammation and RV‐induced exacerbation models. Interestingly, intranasal administration of CPP‐miR‐146a nanocomplexes reduced HDM‐induced allergic airway inflammation without a significant effect on the Th2/Th1/Th17 balance in wild ‐ type mice. In conclusion, the overexpression of miR‐146a has a strong anti‐inflammatory effect on RV infection in HBECs and a mouse model of allergic airway inflammation, while a lack of miR‐146a/b leads to attenuated type 2 cell responses in mouse models of allergic airway inflammation and RV‐induced exacerbation of allergic airway inflammation. Furthermore, our data indicate that the application of CPP‐miR‐146a nanocomplexes has therapeutic potential for targeting airway inflammation.

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“…For instance, miR-125a can repress inflammation in intestinal mucosa obtained from patients with inflammatory bowel disease (IBD) through modulating E26 transformation-specific-1 (ETS-1) [11]. Previously, accumulating studies elucidated that miRNAs are involved in various aspects of psoriasis, such as mediating inflammatory responses and regulating cell functions in keratinocytes [12, 13]. These findings all suggest that miR-125a is intimately related to the inflammation and immunity regulation.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-125a Correlates with Decreased Psoriasis Severity and Inflammation and Represses Keratinocyte Proliferation

2021

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Background: Psoriasis has a complex etiology related to inflammation and dysregulated immune system. MicroRNA (miR)-125a is a miRNA intimately related to inflammation and immunity; therefore, we presumed that it might play a role in the pathogenesis of psoriasis. This study aimed to investigate the correlation of miR-125a with disease severity and inflammation in psoriasis patients, and the effect of miR-125a on proliferation, apoptosis as well as its target signaling pathway in keratinocytes. Methods: Sixty psoriasis patients were consecutively recruited, then lesional and non-lesional skin tissue samples were collected. miR-125a in lesional and non-lesional skin tissues, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-17 mRNA expressions in lesional skin tissues were detected. Then, miR-125a overexpression, control overexpression, miR-125a knockdown and control knockdown plasmids were transfected into HaCaT cells. Subsequently, cell proliferation, apoptosis, IL-23R, JAK2, and STAT3 expressions were assessed. Results: miR-125a was reduced in lesional skin tissue compared with non-lesional skin tissue (p < 0.001), and it distinguished lesional skin tissue from non-lesional skin tissue with a high area under curve of 0.917 (95% CI 0.866–0.968). Negative association of miR-125a in lesional skin tissue with lesional body surface area (p = 0.037) and psoriasis area and severity index score (p < 0.001) was found. Additionally, miR-125a was negatively correlated with TNF-α (p = 0.001), IL-1β (p = 0.014), and IL-17 (p = 0.003) in lesional skin tissue. In cellular experiments, miR-125a overexpression inhibited proliferation and promoted apoptosis, while miR-125a knockdown enhanced proliferation and repressed apoptosis in HaCaT cells. Additionally, miR-125a negatively regulated the IL-23R/JAK2/STAT3 pathway in HaCaT cells. Conclusion: miR-125a could facilitate the disease monitoring and probably has the potential to be a therapeutic target in psoriasis.

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

Cited by 24 publications

References 63 publications

HMSC-Derived Exosome Inhibited Th2 Cell Differentiation via Regulating miR-146a-5p/SERPINB2 Pathway

HMSC-Derived Exosome Inhibited Th2 Cell Differentiation via Regulating miR-146a-5p/SERPINB2 Pathway

Dual role of the miR‐146 family in rhinovirus‐induced airway inflammation and allergic asthma exacerbation

MicroRNA-125a Correlates with Decreased Psoriasis Severity and Inflammation and Represses Keratinocyte Proliferation

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