Metabolic rewiring in keratinocytes by miR-31-5p identifies therapeutic intervention for psoriasis.

Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR-31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

The Role of Th17/Treg Axis in the Traditional Chinese Medicine Intervention on Immune-Mediated Inflammatory Diseases: A Systematic Review.

The Th17/Treg axis plays a crucial role in immune-mediated inflammatory diseases (IMID) and might represent an interesting drug target of treatment strategy for these diseases. Accumulating evidence suggests a role for traditional Chinese medicine (TCM) in the modulation of Th17/Treg axis, but a comprehensive overview which summarizes this field hitherto is lacked. This paper performs a systematic literature review of the regulatory effects of TCM on the imbalance of Th17/Treg axis and its potential mechanisms. In addition, the frequency analysis and network pharmacology for the collected TCM herbs from clinical trial data were performed. The studies reported the changes in the ratio of Th17 and/or Treg cells as well as their transcription factor and related cytokines were included. Frequency analysis of composition of the 39 assessed TCM prescriptions showed that Astragalus membranaceus var.mongholicus (5.20%), Glycyrrhiza uralensis (3.67%), Paeonia obovate (3.06%), Salvia digitaloides (3.06%), and Angelica sinensis (2.75%) were the top five herbal components, which were closely associated to the treatment of IMID. Network pharmacology showed that six target proteins (transforming growth factor (TGF)-beta receptor type-1, TGF-beta receptor type-2, retineic-acid-receptor-related orphan nuclear receptor gamma (ROR-gamma), TGFB2, IL-17 and IL-2, respectively) might be involved in the regulatory effects of TCM on Th17/Treg axis. Moreover, there were nine active ingredients (including Oxymatrine, Baicalin, Triptolide, Paeoniflorin, Sinomenine, Celastrol, Emodin, Diosgenin and Chlorogenic acid) originating from TCM reported to have an immunological regulation effect on the Th17/Treg axis. The highlight of this systematic review is to reveal the pharmacological basis of TCM treating IMID and is helpful for supporting future pharmacologic-driven studies. Further research elucidates the immune-modulating mechanisms on Th17/Treg axis by TCM might provide a broader insight for the treatment of IMID.

Betulinic acid suppresses Th17 response and ameliorates psoriasis-like murine skin inflammation.

Psoriasis is a common inflammatory skin disease. Current treatment for psoriasis relies on conventional immunosuppressive agents. However, long-term treatment with global immunosuppression may cause various side effects. Thus, it is compelling to seek alternative drugs for treating psoriasis with potentially less side effects. Betulinic acid (BA) is a naturally occurring pentacyclic triterpene, an ingredient that originally exists in natural plants and lacks systemic toxicity. BA can regulate immunity with anti-fibrotic, anti-inflammatory and antioxidant properties. However, it's unknown whether BA has a therapeutic effect on psoriasis. The objectives of this study were to investigate whether BA attenuates psoriatic skin inflammation and to identify its mechanisms of action. A murine model of imiquimod-induced psoriasis was utilized to evaluate skin lesion while flow cytometry, immunohistochemistry, quantitative RT-PCR and Western blotting analyses were performed for immunoassays. We found that BA treatment alleviated psoriatic symptoms and inflammatory skin lesion. BA lowered the PASI scores, decreased epidermal thickness and reduced T cell infiltration in the skin lesion. Moreover, BA reduced the frequency of IL-17A-expressing CD4+ and γδ T cells in psoriatic mice, but did not alter CD4+FoxP3+ Treg frequency. BA also reduced IL-17A production but increased anti-inflammatory cytokine IL-10 level in serum of the psoriatic mice. Furthermore, BA inhibited gene expression of pro-inflammatory mediators in skin lesions, including RORγt, IL-17A, IL-6 and TNFα. Importantly, it suppressed NFκB signaling in the skin lesion. Finally, BA inhibited T cell proliferation and IL-17A production by CD4+ T-Cells in vitro. Thus, BA attenuates psoriasis and inhibits Th17 development.

Role of an imbalanced miRNAs axis in pathogenesis of psoriasis: novel perspectives based on review of the literature.

BACKGROUND: Specific profile of microRNAs (miRNAs, miR) expressed in psoriasis has been identified in the past few years, while the studies on roles and molecular mechanisms of these miRNAs are still on the way. In our previous study, four specific miRNAs (miR-31, miR-203, hsa-miR-99a and miR-125b) were found to be specifically altered in psoriatic lesions.We therefore conducted a systematic literature review in this study to reveal the role of these miRNAs in the pathogenesis of psoriasis in order to inform future research. METHODS: The related articles indexed in PubMed (MEDLINE) database were searched and analyzed. We identified eligible studies related to the mechanism research of miR-31, miR-203, hsa-miR-99a and miR-125b in psoriasis or psoriatic lesional skin from inception up to July 2016. The experts in the field of miRNAs and Psoriasis were involved in analysis process. RESULTS: Both miR-31 and miR-203 are dramatically upregulated in psoriatic lesions. The former plays the pro-proliferative, pro-differentiative and pro-inflammatory roles and the latter holds the potentials for anti-proliferation, pro-inflammation and pro-differentiation in psoriatic keratinocytes. Conversely, both hsa-miR-99a and miR-125b are significantly downregulated in psoriatic skin. These two miRNAs are able to inhibit proliferation while promote differentiation of psoriatic keratinocytes, and miR-125b can also suppress inflammation in psoriatic lesions. By analyzing the contexts related to these miRNAs, we found that each of them does not act alone but rather work in concert with other miRNAs. The imbalance between miR-31/miR-203and hsa-miR-99a/miR-125b may contribute to the intense proliferation and abnormal differentiation of psoriatic keratinocytes, which is a characteristic of pathogenesis of psoriasis. CONCLUSION: An imbalanced miRNAs axis was for the first time outlined. Apparently, upregulation of miR-31/miR-203 and downregulation of hsa-miR-99a/miR-125b work together in concert to facilitate the development of psoriasis pathogenesis. Further work in this field holds the potentials to open a new way to study psoriasis.

Role of gut microbiome in ankylosing spondylitis: an analysis of studies in literature.

OBJECTIVE: Gut microbiome is considered to be involved in the pathogenesis of ankylosing spondylitis (AS). We conducted a comprehensive literature review in this area to facilitate future research. METHODS: We searched all literature in the PubMed database from inception to July 2016. Relevant articles were chosen and analyzed by three independent investigators. RESULTS: The composition of gut microbiome in patients with AS has been identified to be different from healthy populations; however, specific profiles of gut microbiome are not yet clearly known. Through the host-bacteria dynamic interactions in general, intestinal dysbiosis impairs the gut mucosal barrier and leads to the disorder of intestinal mucosal immunity, resulting in increased pro-inflammatory cytokines and subsequent chronic inflammatory phenotype of AS. Moreover, colonization with specific AS gut microbiome could induce effective animal models, which will aid studies of pathogenesis of AS. CONCLUSION: This analysis underscores the role of gut microbiome in chronic inflammation of AS and its possible underlying mechanisms. Intestinal dysbiosis is undoubtedly involved in the disease progression of AS, and the discovery of a specific profile of gut microbiome in AS will help reveal new therapeutic targets and diagnosis markers.

Bushen-Qiangdu-Zhilv decoction inhibits osteogenic differentiation of rat fibroblasts by regulating connexin 43.

Bushen-Qiangdu-Zhilv (BQZ) decoction is a traditional Chinese medicinal compound widely used for treating ankylosing spondylitis (AS). However, the mechanisms underlying effects of BQZ remain largely unknown. Osteoblast differentiation of fibroblasts plays an important role in heterotopic ossification (HO) of AS, and connexin 43 (Cx43) is crucially involved in the osteoblast differentiation of fibroblasts. The aim of the present study was to evaluate the effects of BQZ on the osteogenic differentiation of fibroblasts by regulating Cx43. Rat fibroblasts were treated with freeze-dried powder of BQZ, in the presence or absence of recombinant human bone morphogenetic protein-2 (rhBMP-2). MTS assays were performed to examine the inhibitory effects of BQZ on fibroblast proliferation. Western blot assays were conducted to detect the protein expression of core-binding factor alpha 1 (Cbfα1), Cx43 and phosphorylated Cx43 (pCx43). BQZ appeared to inhibit fibroblast proliferation in a dose-dependent manner. Furthermore, the expression of Cbfα1 and Cx43/pCx43 was significantly suppressed by BQZ, with or without rhBMP-2 stimulation. Therefore, the present results indicate that BQZ may exert an anti-AS effect by suppressing the osteogenic differentiation of fibroblasts via Cx43 regulation.