miR-424(322) is a molecular switch controlling pro-inflammatory vs anti-inflammatory skin DC subset differentiation by modulating TGF-β signaling

AbstractTGF-β family ligands are key regulators of dendritic cell (DC) differentiation and activation. Epidermal Langerhans cells (LCs) require TGF- β family signaling for their differentiation and canonical TGF-β1 signaling secures a non-activated LC state. LCs reportedly control skin inflammation and are replenished from peripheral blood monocytes, which also give rise to pro-inflammatory monocyte-derived DCs (moDCs). Among all the miRNAs differentially expressed in LC vs moDCs, we observed miR-424 to be strongly induced during moDC differentiation from monocytes. We discovered that miR-424 is required for moDC differentiation from human and murine precursor cells in vitro and for inflammation-associated moDC in vivo. Mechanistically we found that low levels of miR-424 facilitate TGF-β1-dependent LC differentiation at the expense of moDC differentiation. Loss of miR-424 in monocyte/DC precursors resulted in the induction of TGF-β pathway. Therefore, miR-424 plays a decisive role in anti-inflammatory LC vs pro-inflammatory moDC differentiation from monocytes, and its repression allows TGF-β ligands to promote LC differentiation.Short summaryMonocytes give rise to two distinct DC subsets in skin inflammation, exhibiting opposite roles in inflammation. This study identified miR-424(322) as a molecular switch controlling pro-inflammatory (moDC) vs anti-inflammatory LC subset differentiation by modulating TGF-β signaling.

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Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol antioxidant Nacystelyn

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00329.2003 ◽

2004 ◽

Vol 286 (6) ◽

pp. L1319-L1327 ◽

Cited By ~ 44

Author(s):

Frank Antonicelli ◽

David Brown ◽

Maryline Parmentier ◽

Ellen M. Drost ◽

Nik Hirani ◽

...

Keyword(s):

Dna Binding ◽

Transforming Growth Factor ◽

Lavage Fluid ◽

Human Macrophage ◽

Antioxidant Agents ◽

Thiol Antioxidant ◽

Anti Inflammatory ◽

Tgf Β1

Increased levels of proinflammatory cytokines are present in bronchoalveolar lavage fluid in various lung diseases. Redox-sensitive transcription factors such as NF-κB regulate gene transcription for these cytokines. We therefore studied the effect of a new thiol antioxidant compound, Nacystelyn (NAL), on IL-8 regulation in a human macrophage-derived cell line (THP-1). LPS (10 μg/ml) increased IL-8 release compared with control levels. This LPS activation was inhibited by coincubation with NAL (1 and 5 mM). Pretreatment with cycloheximide or okadaic acid, protein synthesis, and serine/threonine phosphatase inhibitors, respectively, did not modify inhibition of IL-8 release caused by NAL. NF-κB and C/EBP DNA binding were increased after LPS treatment compared with control, an effect inhibited by cotreatment with NAL. Activator protein (AP)-1 DNA binding was unaffected. The enhanced neutrophil chemotaxis produced by conditioned media from LPS-treated cells was inhibited when cells were cotreated with NAL. The selectivity of NAL inhibition upon IL-8 expression was studied. LPS-treated THP-1 cells also had higher levels of TNF-α, transforming growth factor (TGF)-β1 and -3, MIP-1α and -β, and RANTES gene expression. However, only LPS-induced IL-8 and TGF-β1 expressions were inhibited by NAL. An anti-inflammatory effect of NAL was confirmed in vivo as shown by a reduction in LPS-induced neutrophil recruitment to the lungs following instillation of NAL into the lungs. Our studies demonstrate that NAL has anti-inflammatory properties in vitro and in vivo, may therefore have a therapeutic role in lung inflammation, and has the advantage over other antioxidant agents in that it may be administrated by inhalation.

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In vitro and in vivo investigation of polypharmacology of propolis extract as anticancer, antibacterial, anti-inflammatory, and chemical properties

Open Chemistry ◽

10.1515/chem-2021-0076 ◽

2021 ◽

Vol 19 (1) ◽

pp. 864-874

Author(s):

Nael Abutaha ◽

Mohammed AL-Zharani ◽

Amal Alotaibi ◽

Mary Anne W. Cordero ◽

Asmatanzeem Bepari ◽

...

Keyword(s):

Chemical Properties ◽

Acid Methyl Ester ◽

Cost Effective ◽

Skin Inflammation ◽

Hexane Extract ◽

Major Constituent ◽

Propolis Extract ◽

Anti Inflammatory

Abstract Numerous compounds derived from natural sources such as microbes, plants, and insects have proven to be safe, efficacious, and cost-effective therapeutics for human diseases. This study examined the bioactivities of propolis, a structural sealant and antibacterial/antifungal agent produced by honey bees. Chinese propolis was extracted in methanol or hexane. Propolis significantly reduced the numbers of viable cancer cells when applied as a methanol extract (IC50 values in μg/mL for the indicated cell line: MDA-MB-231, 74.12; LoVo, 74.12; HepG2, 77.74; MCF7, 95.10; A549, 114.84) or a hexane extract (MDA-MB-231, 52.11; LoVo, 45.9; HepG2, 52.11; MCF7, 78.01; A549, 67.90). Hexane extract also induced apoptosis of HepG2 cells according to activated caspase-3/7 expression assays (17.6 ± 2.9% at 150 μg/mL and 89.2 ± 1.9% at 300 μg/mL vs 3.4 ± 0.4% in vehicle control), suppressed the growth of Candida albicans and multiple multidrug-resistant and nonresistant Gram-positive bacteria, and inhibited croton oil-induced skin inflammation when applied as topical treatment. GC-MS identified hexadecanoic acid methyl ester as a major constituent (33.6%). Propolis hexane extract has potential anticancer, antimicrobial, and anti-inflammatory activities.

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Identification of bone morphogenetic protein 7 (BMP7) as an instructive factor for human epidermal Langerhans cell differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20130275 ◽

2013 ◽

Vol 210 (12) ◽

pp. 2597-2610 ◽

Cited By ~ 68

Author(s):

Nighat Yasmin ◽

Thomas Bauer ◽

Madhura Modak ◽

Karin Wagner ◽

Christopher Schuster ◽

...

Keyword(s):

Bone Morphogenetic Protein ◽

Prenatal Development ◽

Langerhans Cell ◽

Type I ◽

Blood Monocytes ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein ◽

Tgf Β1

Human Langerhans cell (LC) precursors populate the epidermis early during prenatal development and thereafter undergo massive proliferation. The prototypic antiproliferative cytokine TGF-β1 is required for LC differentiation from human CD34+ hematopoietic progenitor cells and blood monocytes in vitro. Similarly, TGF-β1 deficiency results in LC loss in vivo. However, immunohistology studies revealed that human LC niches in early prenatal epidermis and adult basal (germinal) keratinocyte layers lack detectable TGF-β1. Here we demonstrated that these LC niches express high levels of bone morphogenetic protein 7 (BMP7) and that Bmp7-deficient mice exhibit substantially diminished LC numbers, with the remaining cells appearing less dendritic. BMP7 induces LC differentiation and proliferation by activating the BMP type-I receptor ALK3 in the absence of canonical TGF-β1–ALK5 signaling. Conversely, TGF-β1–induced in vitro LC differentiation is mediated via ALK3; however, co-induction of ALK5 diminished TGF-β1–driven LC generation. Therefore, selective ALK3 signaling by BMP7 promotes high LC yields. Within epidermis, BMP7 shows an inverse expression pattern relative to TGF-β1, the latter induced in suprabasal layers and up-regulated in outer layers. We observed that TGF-β1 inhibits microbial activation of BMP7-generated LCs. Therefore, TGF-β1 in suprabasal/outer epidermal layers might inhibit LC activation, resulting in LC network maintenance.

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Anti-Inflammatory Effects of Alnus Sibirica Extract on In Vitro and In Vivo Models

Molecules ◽

10.3390/molecules25061418 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1418

Author(s):

Jeongyoon Choi ◽

Sunghee Moon ◽

Hyemi Bae ◽

Young-Won Kim ◽

Yelim Seo ◽

...

Keyword(s):

Immunoglobulin E ◽

Skin Inflammation ◽

Skin Lesions ◽

Dermal Fibroblasts ◽

In Vivo Model ◽

Necrosis Factor Alpha ◽

In Vivo Models ◽

Anti Inflammatory

Alnus sibirica extracts (ASex) have long been used in Oriental medicine to treat various conditions. To provide a scientific basis for this application and the underlying mechanism, we investigated the anti-inflammatory effects of ASex in vitro and in vivo. The in vitro model was established using human dermal fibroblasts (HDFs) treated with inflammatory stimulants (lipopolysaccharide, tumor necrosis factor-alpha, interferon-gamma). Lactate dehydrogenase and reverse transcription-polymerase chain reaction showed that ASex inhibited the increased expression of acute-phase inflammatory cytokines. The in vivo model was established by inducing skin inflammation in NC/Nga mice via the repeated application of house dust mite (HDM) ointment to the ears and back of the mice for eight weeks. HDM application increased the severity of skin lesions, eosinophil/mast cell infiltration, and serum immunoglobulin E levels, which were all significantly decreased by ASex treatment, demonstrating the same degree of protection as hydrocortisone. Overall, ASex showed excellent anti-inflammatory effects both in vitro and in vivo, suggesting its potential as an excellent candidate drug to reduce skin inflammation.

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Inhibition of Skin Inflammation by Scytonemin, an Ultraviolet Sunscreen Pigment

Marine Drugs ◽

10.3390/md18060300 ◽

2020 ◽

Vol 18 (6) ◽

pp. 300

Author(s):

Moo Rim Kang ◽

Sun Ah Jo ◽

Hyunju Lee ◽

Yeo Dae Yoon ◽

Joo-Hee Kwon ◽

...

Keyword(s):

Nitric Oxide ◽

Nuclear Translocation ◽

Skin Inflammation ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Blue Green Algae ◽

Tnf Α ◽

Anti Inflammatory

Scytonemin is a yellow-green ultraviolet sunscreen pigment present in different genera of aquatic and terrestrial blue-green algae, including marine cyanobacteria. In the present study, the anti-inflammatory activities of scytonemin were evaluated in vitro and in vivo. Topical application of scytonemin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear swelling in BALB/c mice. The expression of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) was also suppressed by scytonemin treatment in the TPA-treated ear of BALB/c mice. In addition, scytonemin inhibited lipopolysaccharide (LPS)-induced production of TNF-α and nitric oxide (NO) in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expressions of TNF-α and iNOS were also suppressed by scytonemin in LPS-stimulated RAW 264.7 cells. Further study demonstrated that LPS-induced NF-κB activity was significantly suppressed by scytonemin treatment in RAW 264.7 cells. Our results also showed that the degradation of IκBα and nuclear translocation of the p65 subunit were blocked by scytonemin in LPS-stimulated RAW 264.7 cells. Collectively, these results suggest that scytonemin inhibits skin inflammation by blocking the expression of inflammatory mediators, and the anti-inflammatory effect of scytonemin is mediated, at least in part, by down-regulation of NF-κB activity. Our results also suggest that scytonemin might be used as a multi-function skin care ingredient for UV protection and anti-inflammation.

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Apremilast Microemulsion as Topical Therapy for Local Inflammation: Design, Characterization and Efficacy Evaluation

Pharmaceuticals ◽

10.3390/ph13120484 ◽

2020 ◽

Vol 13 (12) ◽

pp. 484

Author(s):

Paulo Sarango-Granda ◽

Marcelle Silva-Abreu ◽

Ana Calpena ◽

Lyda Halbaut ◽

María-José Fábrega ◽

...

Keyword(s):

Topical Therapy ◽

Skin Inflammation ◽

In Vivo Model ◽

Order Kinetic ◽

Efficacy Evaluation ◽

In Vivo Models ◽

Local Skin ◽

Anti Inflammatory

Apremilast (APR) is a selective phosphodiesterase 4 inhibitor administered orally in the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. The low solubility and permeability of this drug hinder its dermal administration. The purpose of this study was to design and characterize an apremilast-loaded microemulsion (APR-ME) as topical therapy for local skin inflammation. Its composition was determined using pseudo-ternary diagrams. Physical, chemical and biopharmaceutical characterization were performed. Stability of this formulation was studied for 90 days. Tolerability of APR-ME was evaluated in healthy volunteers while its anti-inflammatory potential was studied using in vitro and in vivo models. A homogeneous formulation with Newtonian behavior and droplets of nanometric size and spherical shape was obtained. APR-ME released the incorporated drug following a first-order kinetic and facilitated drug retention into the skin, ensuring a local effect. Anti-inflammatory potential was observed for its ability to decrease the production of IL-6 and IL-8 in the in vitro model. This effect was confirmed in the in vivo model histologically by reduction in infiltration of inflammatory cells and immunologically by decrease of inflammatory cytokines IL-8, IL-17A and TNFα. Consequently, these results suggest that this formulation could be used as an attractive topical treatment for skin inflammation.

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Anti-Inflammatory Effect of Mallotus Philippinensis Bark Extracts in a Mouse Atopic Dermatitis Model

Journal of Clinical Research in Dermatology ◽

10.15226/2378-1726/7/1/001110 ◽

2020 ◽

Vol 7 (1) ◽

pp. 1-8

Author(s):

Sae Asayama ◽

Ayaka Iwasaki ◽

Shunya Sahara ◽

Koichi Nakaoji ◽

Masamitsu Ichihashi ◽

...

Keyword(s):

Atopic Dermatitis ◽

Inflammatory Diseases ◽

Radical Scavenging ◽

Skin Inflammation ◽

In Vivo Model ◽

Anti Inflammatory ◽

Anti Inflammation ◽

Inflammatory Effect

Background: Atopic Dermatitis (AD) is a chronic inflammatory skin disease that causes functional disruption of the skin barrier. We previously found that ethanol Extracts of Mallotus Philippinensis Bark (EMPB) promoted migration of mesenchymal stem cells and improved wound healing probably through anti-inflammatory action. However, direct evidence of the anti-inflammatory effect of EMPB and the underlying mechanisms of this action remain unknown. In the present study, we evaluated whether EMPB has an effective action on anti-inflammation using an in vitro and in vivo model. We found that topical application of EMPB improved house dust miteinduced AD-like skin inflammation in NC/Nga mice. In addition, EMPB significantly inhibited various kinds of inflammatory mediators such as interleukin-1ß, inducible nitric oxide synthases, and nuclear factorkappa B in lipopolysaccharide-stimulated macrophage cells. Moreover, EMPB exhibited marked radical scavenging ability. Taken together, these results suggest that EMPB may be useful in the treatment of skin inflammatory diseases such as AD. Keywords: Mallotus Philippinensis Bark; Anti-Inflammation; Atopic Dermatitis; Macrophages

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Inhibitory Effects of a Novel Chrysin-Derivative, CPD 6, on Acute and Chronic Skin Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20112607 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2607 ◽

Cited By ~ 3

Author(s):

Chan-Hee Yu ◽

Beomseon Suh ◽

Iljin Shin ◽

Eun-Hye Kim ◽

Donghyun Kim ◽

...

Keyword(s):

Skin Diseases ◽

Human Keratinocytes ◽

Skin Inflammation ◽

Inflammatory Reactions ◽

Tnf Α ◽

Anti Inflammatory ◽

Chronic Skin ◽

External Stimuli

The skin is an important physiological barrier against external stimuli, such as ultraviolet radiation (UV), xenobiotics, and bacteria. Dermal inflammatory reactions are associated with various skin disorders, including chemical-induced irritation and atopic dermatitis. Modulation of skin inflammatory response is a therapeutic strategy for skin diseases. Here, we synthesized chrysin-derivatives and identified the most potent derivative of Compound 6 (CPD 6). We evaluated its anti-inflammatory effects in vitro cells of macrophages and keratinocytes, and in vivo dermatitis mouse models. In murine macrophages stimulated by lipopolysaccharide (LPS), CPD 6 significantly attenuated the release of inflammatory mediators such as nitric oxide (NO) (IC50 for NO inhibition: 3.613 μM) and other cytokines. In cultured human keratinocytes, CPD 6 significantly attenuated the release of inflammatory cytokines induced by the combination of IFN-γ and TNF-α, UV irradiation, or chemical irritant stimulation. CPD 6 inhibited NFκB and JAK2/STAT1 signaling pathways, and activated Nrf2/HO-1 signaling. In vivo relevancy of anti-inflammatory effects of CPD 6 was observed in acute and chronic skin inflammation models in mice. CPD 6 showed significant anti-inflammatory properties both in vitro cells and in vivo dermatitis animal models, mediated by the inhibition of the NFκB and JAK2-STAT1 pathways and activation of Nrf2/HO-1 signaling. We propose that the novel chrysin-derivative CPD 6 may be a potential therapeutic agent for skin inflammation.

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