IL-23 induces CLEC5A+ IL-17A+ neutrophils and elicit skin inflammation associated with psoriatic arthritis.

IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23RGFP reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1+CD11b+Ly6G+ population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23R+MDL1+ cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity.

Interleukin-23 Regulates Inflammatory Osteoclastogenesis via Activation of CLEC5A(+) Osteoclast Precursors.

OBJECTIVE: To investigate the role of interleukin-23 (IL-23) in pathologic bone remodeling in inflammatory arthritis. METHODS: In this study we investigated the role of IL-23 in osteoclast differentiation and activation using in vivo gene transfer techniques in wild-type and myeloid DNAX-activation protein 12-associating lectin-1 (MDL-1)-deficient mice, and by performing in vitro and in vivo osteoclastogenesis assays using spectral flow cytometry, micro-computed tomography analysis, Western blotting, and immunoprecipitation. RESULTS: Herein, we show that IL-23 induces the expansion of a myeloid osteoclast precursor population and supports osteoclastogenesis and bone resorption in inflammatory arthritis. Genetic ablation of C-type lectin domain family member 5A, also known as MDL-1, prevents the induction of osteoclast precursors by IL-23 that is associated with bone destruction, as commonly observed in inflammatory arthritis. Moreover, osteoclasts derived from the bone marrow of MDL-1-deficient mice showed impaired osteoclastogenesis, and MDL-1-/- mice had increased bone mineral density. CONCLUSION: Our data show that IL-23 signaling regulates the availability of osteoclast precursors in inflammatory arthritis that could be effectively targeted for the treatment of inflammatory bone loss in inflammatory arthritis.

Peripheral γδ T Cells Regulate Neutrophil Expansion and Recruitment in Experimental Psoriatic Arthritis.

OBJECTIVE: This study was undertaken to identify the mechanistic role of γδ T cells in the pathogenesis of experimental psoriatic arthritis (PsA). METHODS: In this study, we performed interleukin-23 (IL-23) gene transfer in wild-type (WT) and T cell receptor δ-deficient (TCRδ-/- ) mice and conducted tissue phenotyping in the joint, skin, and nails to characterize the inflammatory infiltrate. We further performed detailed flow cytometry, immunofluorescence staining, RNA sequencing, T cell repertoire analysis, and in vitro T cell polarization assays to identify regulatory mechanisms of γδ T cells. RESULTS: We demonstrated that γδ T cells support systemic granulopoiesis, which is critical for murine PsA-like pathology. Briefly, γδ T cell ablation inhibited the expression of neutrophil chemokines CXCL1 and CXCL2 and neutrophil CD11b+Ly6G+ accumulation in the aforementioned PsA-related tissues. Although significantly reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A was detected systemically in TCRδ-/- mice, no GM-CSF+/IL-17A+ γδ T cells were detected locally in the inflamed skin or bone marrow in WT mice. Our data showed that nonresident γδ T cells regulate the expansion of an CD11b+Ly6G+ neutrophil population and their recruitment to joint and skin tissues, where they develop hallmark pathologic features of human PsA. CONCLUSION: Our findings do not support the notion that tissue-resident γδ T cells initiate the disease but demonstrate a novel role of γδ T cells in neutrophil regulation that can be exploited therapeutically in PsA patients.

Pharmacological properties of ginsenosides in inflammation-derived cancers.

Ginseng is commonly used as an herbal medicine for improvement of life quality. It is also used as a supplemental medication with anti-cancer drugs to enhance chemotherapy efficacy and shows some beneficial effects. Ginsenosides, also known as saponins, are the major active pharmacological compounds found in ginseng and have been extensively using in treatment of not only cancers but also the other inflammatory diseases such as atherosclerosis, diabetes, acute lung injury, cardiovascular, and infectious diseases. The anti-cancer activities of ginsengs and ginsenosides in different types of cancers have been well studied experimentally and clinically. The major anti-cancer mechanisms of ginseng compounds include inhibition of angiogenesis and metastasis as well as induction of cell cycle arrest and apoptosis. Herein, we review and summarize the current knowledge on the pharmacological effects of ginsengs and ginseng-derived compounds in the treatment of cancers. Moreover, the molecular and cellular mechanism(s) by which ginsengs and ginsenosides modulate the immune response in cancer diseases as well as ginsengs-drugs interaction are also discussed.

Potential therapeutic and pharmacological effects of Wogonin: an updated review.

Flavonoids are members of polyphenolic compounds, which are naturally presented in fruits, vegetables, and some medicinal plants. Traditionally, the root of Scutellaria baicalensis is widely used as Chinese herbal medicine and contains several major bioactive compounds such as Wogonin, Scutellarein, Baicalein, and Baicalin. Experimental and clinical evidence has been proving that Wogonin exhibits diverse biological activities such as anti-cancer, anti-inflammation, and treatment of bacterial and viral infections. In this review, we summarize and emphasize the benefits of Wogonin as a therapeutic adjuvant for anti-viral infection, anti-inflammation, neuroprotection as well as anxiolytic and anticonvulsant. Moreover, the molecular mechanism(s) how Wogonin mediates the cellular signal pathways and immune responses are also discussed and highlighted valuable properties of Wogonin in multiple therapies.

Homeostasis of histone acetylation is critical for auxin signaling and root morphogenesis.

KEY MESSAGE: The auxin signaling and root morphogenesis are harmoniously controlled by two counteracted teams including (1) auxin/indole-3-acetic acid (AUX/IAA)-histone deacetylase (HDA) and (2) auxin response factor (ARF)-histone acetyltransferase (HAT). The involvement of histone acetylation in the regulation of transcription was firstly reported a few decades ago. In planta, auxin is the first hormone group that was discovered and it is also the most studied phytohormone. Current studies have elucidated the functions of histone acetylation in the modulation of auxin signaling as well as in the regulation of root morphogenesis under both normal and stress conditions. Based on the recent outcomes, this review is to provide a hierarchical view about the functions of histone acetylation in auxin signaling and root morphogenesis. In this report, we suggest that the auxin signaling must be controlled harmoniously by two counteracted teams including (1) auxin/indole-3-acetic acid (AUX/IAA)-histone deacetylase (HDA) and (2) auxin response factor (ARF)-histone acetyltransferase (HAT). Moreover, the balance in auxin signaling is very critical to contribute to normal root morphogenesis.

Superoxide Dismutase 3 Inhibits LL-37/KLK-5-Mediated Skin Inflammation through Modulation of EGFR and Associated Inflammatory Cascades.

The expressions of LL-37 and KLK-5 were found to be altered in various dermatoses, including atopic dermatitis, psoriasis, and rosacea. However, the downstream inflammatory effect of LL-37 and KLK-5 is not as well studied. In addition, there is little high-quality evidence for the treatment of LL-37- and KLK-5-mediated inflammation. In this study, we investigated the effect of superoxide dismutase 3 (SOD3) on LL-37- or KLK-5-induced skin inflammation in vitro and in vivo and its underlying anti-inflammatory mechanisms. Our data showed that SOD3 significantly reduced both LL-37- and KLK-5-induced expression of pro-inflammatory mediators and suppressed the activation of EGFR, protease-activated receptor 2, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, and p38/extracellular signal-regulated kinase signaling pathways in human keratinocytes. Moreover, SOD3 suppressed LL-37-induced expression of inflammatory mediators, reactive oxygen species production, and p38/extracellular signal-regulated kinase activation in mast cells. In addition, subcutaneous injection of KLK-5 in SOD3 knockout mice exhibited erythema with increased epidermal thickness, mast cell and neutrophil infiltration, expression of inflammatory mediators, and activation of EGFR, protease-activated receptor 2, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, and downstream mitogen-activated protein kinase pathways. However, treatment with SOD3 in SOD3 knockout mice rescued KLK-5-induced inflammatory cascades. Similarly, KLK-5-induced inflammation in wild-type mice was also ameliorated when treated with SOD3. Taken together, our data suggest that SOD3 is a potentially effective therapy for both LL-37-and KLK-5-induced skin inflammation.

Anti-oxidative effects of superoxide dismutase 3 on inflammatory diseases.

Free radicals and other oxidants are critical determinants of the cellular signaling pathways involved in the pathogenesis of several human diseases including inflammatory diseases. Numerous studies have demonstrated the protective effects of antioxidant enzymes during inflammation by elimination of free radicals. The superoxide dismutase (SOD), an antioxidant enzyme, plays an essential pathogenic role in the inflammatory diseases by not only catalyzing the conversion of the superoxide to hydrogen peroxide and oxygen but also affecting immune responses. There are three distinct isoforms of SOD, which distribute in different cellular compartments such as cytosolic SOD1, mitochondrial SOD2, and extracellular SOD3. Many studies have investigated the anti-oxidative effects of SOD3 in the inflammatory diseases. Herein, in this review, we focus on the current understanding of SOD3 as a therapeutic protein in inflammatory diseases such as skin, autoimmune, lung, and cardiovascular inflammatory diseases. Moreover, the mechanism(s) by which SOD3 modulates immune responses and signal initiation in the pathogenesis of the diseases will be further discussed.

The MYB-bHLH-WDR interferers (MBWi) epigenetically suppress the MBW's targets.

Active repressors have been evidenced to function in different plant growth and development programs including hormonal signalling pathways. In Arabidopsis, the MYB-bHLH-WDR (MBW) complex is known to regulate different phenotypic traits such as anthocyanin biosynthesis, seed coat colour, trichome and root hair patterning. A number of transcription factors have been identified to play a negative role in the regulation of these traits via the interruption of MBW formation and function. Since these transcription factors work to interfere with the MBW complex, this review suggests their general name as MBW interferers (MBWi). Recent studies have shed light on the molecular mechanism of these MBWi and this review is aiming to provide a precise view of these MBWi. Moreover, from these, a new characteristic of active repressors is also updated.

γδ T cells in rheumatic diseases: from fundamental mechanisms to autoimmunity.

The innate and adaptive arms of the immune system tightly regulate immune responses in order to maintain homeostasis and host defense. The interaction between those two systems is critical in the activation and suppression of immune responses which if unchecked may lead to chronic inflammation and autoimmunity. γδ T cells are non-conventional lymphocytes, which express T cell receptor (TCR) γδ chains on their surface and straddle between innate and adaptive immunity. Recent advances in of γδ T cell biology have allowed us to expand our understanding of γδ T cell in the dysregulation of immune responses and the development of autoimmune diseases. In this review, we summarize current knowledge on γδ T cells and their roles in skin and joint inflammation as commonly observed in rheumatic diseases.

Pharmacological effects of ginseng on infectious diseases.

Ginseng has been traditionally used as an herbal nutritional supplement in Asian countries, including Korea, China, Japan, and Vietnam for several millennia. Most studies have focused on the role of ginseng on anti-oxidative stress, anti-inflammatory, and anti-cancer activities. Recently, modulator activities of ginseng on the immune responses during pathogenic bacterial and viral infections and beneficial effects of ginseng in infectious diseases have been elucidated. In vivo and in vitro studies revealed the potential of ginseng extracts and ginsenosides Rg1, Rg3, Rb1, Rb2, Rb3, compound K, Re, Rd, Rh2 for treatment of several infectious diseases. The molecular mechanisms of these effects mainly involve inflammatory cytokines (TNF-α, IL-6, IL-1ß, IFN-γ, IL-10), apoptotic pathway (bcl-2, bcl-xL), PI3K/Akt pathway, MAPKs pathway, JAK2/STAT5, NF-κB pathway, and the inflammasome. In this review, we will summarize the current knowledge on the effects of ginseng in the immune responses during the infections and its bioactivities on the prevention of infectious diseases as well as its underlying mechanisms. Moreover, the therapeutic potential of ginseng as an anti-bacterial and anti-viral medication and vaccine adjuvant will be discussed as well.

Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. In this review, we will discuss recent advances on the cellular and molecular pathophysiological mechanisms that regulate the initiation and progression of PsA as well as new therapeutic approaches for IL-23/IL-23R targeted therapeutics.

Author Correction: Inhibitory effects of superoxide dismutase 3 on Propionibacterium acnes-induced skin inflammation.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Enhanced therapeutic effects of human mesenchymal stem cells transduced with superoxide dismutase 3 in a murine atopic dermatitis-like skin inflammation model.

BACKGROUND: The use of mesenchymal stem cells (MSCs) has been proposed to treat various autoimmune diseases. However, effective strategies for treating atopic dermatitis (AD) are still lacking, and the mechanisms underlying stem cell therapy remain largely unknown. In this study, we sought to explore potential clinical application of superoxide dismutase 3-transduced MSCs (SOD3-MSCs) to experimental AD-like skin inflammation in in vitro and in vivo and its underlying anti-inflammatory mechanisms. METHODS: SOD3-MSCs were administered subcutaneously to mice with AD, and associated symptoms and biologic changes were evaluated. Human keratinocytes, mast cells, and murine T helper (Th) 2 cells were cocultured in vitro with SOD3-MSCs to investigate potential therapeutic effects of SOD3-MSCs. RESULTS: In mice with AD, SOD3-MSCs ameliorated AD pathology and enhanced the efficacy of MSC therapy by controlling activated immune cells, by reducing expression levels of proinflammatory mediators in the skin, and by inhibiting the histamine H4 receptor (H4R)-mediated inflammatory cascade and activation of Janus kinase signal transducer and activator of transcription pathways. Similarly, coculture of SOD3-MSCs with mast cells, keratinocytes, and Th2 cells effectively dampened H4R-dependent persistent inflammatory responses by multiple mechanisms. Moreover, we also showed that SOD3 interacts with H4R and IL-4 receptor α. The functional significance of this interaction could be a markedly reduced inflammatory response in keratinocytes and overall AD pathogenesis, representing a novel mechanism for SOD3's anti-inflammatory effects. CONCLUSION: SOD3-MSCs can be potentially used as an effective and clinically relevant therapy for AD and other autoimmune disorders.

Inhibitory effects of superoxide dismutase 3 on Propionibacterium acnes-induced skin inflammation.

Propionibacterium acnes is a well-known commensal bacterium that plays an important role in the pathogenesis of acne and chronic inflammatory skin disease. In this study, we investigated the effect of superoxide dismutase 3 (SOD3) on P. acnes- or peptidoglycan (PGN)-induced inflammation in vitro and in vivo. Our data demonstrated that SOD3 suppressed toll-like receptor-2 (TLR-2) expression in P. acnes- or PGN-treated keratinocytes and sebocytes. Moreover, we found that SOD3 suppressed the expressions of phosphorylated nuclear factor-κB (NF-κB) and p38 in P. acnes- or PGN-treated cells. SOD3 also exhibited an anti-inflammatory role by reducing the expression of inflammasome-related proteins (NLRP3, ASC, caspase-1) and inhibiting the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, interleukin-6, and interleukin-8. In addition, SOD3 reduced lipid accumulation and expression of lipogenic regulators in P. acnes-treated sebocytes. Recombinant SOD3-treated wild-type mice and SOD3 transgenic mice, which were subcutaneously infected with P. acnes, showed tolerance to inflammation through reducing inflammatory cell infiltration in skin, ear thickness, and expression of inflammatory mediators. Our result showed that SOD3 could suppress the inflammation through inhibition of TLR2/p38/NF-κB axis and NLRP3 inflammasome activation. Therefore, SOD3 could be a promising candidate for treatment of P. acnes-mediated skin inflammation.

Inhibition of Autolysis by Lipase LipA in Streptococcus pneumoniae Sepsis.

More than 50% of sepsis cases are associated with pneumonia. Sepsis is caused by infiltration of bacteria into the blood via inflammation, which is triggered by the release of cell wall components following lysis. However, the regulatory mechanism of lysis during infection is not well defined. Mice were infected with Streptococcus pneumoniae D39 wild-type (WT) and lipase mutant (ΔlipA) intranasally (pneumonia model) or intraperitoneally (sepsis model), and survival rate and pneumococcal colonization were determined. LipA and autolysin (LytA) levels were determined by qPCR and western blotting. S. pneumoniae Spd_1447 in the D39 (type 2) strain was identified as a lipase (LipA). In the sepsis model, but not in the pneumonia model, mice infected with the ΔlipA displayed higher mortality rates than did the D39 WT-infected mice. Treatment of pneumococci with serum induced LipA expression at both the mRNA and protein levels. In the presence of serum, the ΔlipA displayed faster lysis rates and higher LytA expression than the WT, both in vitro and in vivo. These results indicate that a pneumococcal lipase (LipA) represses autolysis via inhibition of LytA in a sepsis model.

Effect of decreased BCAA synthesis through disruption of ilvC gene on the virulence of Streptococcus pneumoniae.

Streptococcus pneumoniae (pneumococcus) is responsible for significant morbidity and mortality worldwide. It causes a variety of life-threatening infections such as pneumonia, bacteremia, and meningitis. In bacterial physiology, the metabolic pathway of branched-chain amino acids (BCAAs) plays an important role in virulence. Nonetheless, the function of IlvC, one of the enzymes involved in the biosynthesis of BCAAs, in S. pneumoniae remains unclear. Here, we demonstrated that downregulation of BCAA biosynthesis by ilvC ablation can diminish BCAA concentration and expression of pneumolysin (Ply) and LytA, and subsequently attenuate virulence. Infection with an ilvC mutant showed significantly reduced mortality and colonization in comparison with strain D39 (serotype 2, wild type), suggesting that ilvC can potentiate S. pneumoniae virulence due to adequate BCAA synthesis. Taken together, these results suggest that the function of ilvC in BCAA synthesis is essential for virulence factor and could play an important role in the pathogenesis of respiratory infections.

Stress responses in Streptococcus species and their effects on the host.

Streptococci cause a variety of diseases, such as dental caries, pharyngitis, meningitis, pneumonia, bacteremia, endocarditis, erysipelas, and necrotizing fasciitis. The natural niche of this genus of bacteria ranges from the mouth and nasopharynx to the skin, indicating that the bacteria will inevitably be subjected to environmental changes during invasion into the host, where it is exposed to the host immune system. Thus, the Streptococcus-host interaction determines whether bacteria are cleared by the host's defenses or whether they survive after invasion to cause serious diseases. If this interaction was to be deciphered, it could aid in the development of novel preventive and therapeutic agents. Streptococcus species possess many virulent factors, such as peroxidases and heat-shock proteins (HSPs), which play key roles in protecting the bacteria from hostile host environments. This review will discuss insights into the mechanism(s) by which streptococci adapt to host environments. Additionally, we will address how streptococcal infections trigger host stress responses; however, the mechanism by which bacterial components modulate host stress responses remains largely unknown.

Panax ginseng aqueous extract prevents pneumococcal sepsis in vivo by potentiating cell survival and diminishing inflammation.

BACKGROUND: More than 50% of sepsis cases are caused by Streptococcus pneumoniae, and hospital mortality related to sepsis comprises 52% of all hospital deaths. Therefore, sepsis is a medical emergency, and any treatment against the agent that produces it, is welcome. PURPOSE: The role of Panax ginseng C.A. Meyer (Araliaceae) aqueous extract in bacterial infection in vivo is not well understood. Here, the protective effect of Korean red ginseng (KRG) extract against pneumococcal infection and sepsis was elucidated. STUDY DESIGN: In this study, mice were administrated KRG (25, 50, 100 mg/kg) for 15 days, and then infected with a lethal S. pneumoniae strain. Survival rate, body weight, and colonization were determined. METHODS: The RAW 264.7 macrophage cells were infected with S. pneumoniae and cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Inflammation was examined using an enzyme-linked immunosorbent assay (ELISA) and hematoxylin and eosin (HE) staining while gene expression was determined using western blotting. RESULTS: KRG-pre-treated mice (100 mg/kg of KRG) had significantly higher survival rates and body weights than those of the non-treated controls; KRG-pre-treated mice had lower bacterial number and morbidity than those of the non-treated controls. 100 mg/kg of KRG administration decreased cytokine levels including tumor necrosis factor (TNF)-α (897 and 623 pg/ml, control and KRG groups, respectively, P < 0.05) and interleukin (IL)-1ß (175 and 127 pg/ml, control and KRG groups, respectively, P = 0.051), nitric oxide level (149 and 81 nM, control and KRG groups, respectively, P < 0.05), and neutrophil infiltration 48 h post-infection, in vivo. In pneumococcal infection, KRG pre-treatment downregulated toll-like receptor (TLR) 4 and TNF-ɑ expressions in RAW 264.7 macrophage cells and increased cell survival by activating phosphoinositide 3-kinase (PI3K)/AKT signaling. CONCLUSION: Taken together, 100 mg/kg of KRG appeared to protect host cells from lethal pneumococcal sepsis by inhibiting inflammation as well as by enhancing bacterial clearance thereby reinforcing cell survival against pneumococcal infection.

Korean Red Ginseng inhibits apoptosis in neuroblastoma cells via estrogen receptor ß-mediated phosphatidylinositol-3 kinase/Akt signaling.

BACKGROUND: Ginseng has been shown to exert antistress effects both in vitro and in vivo. However, the effects of ginseng on stress in brain cells are not well understood. This study investigated how Korean Red Ginseng (KRG) controls hydrogen peroxide-induced apoptosis via regulation of phosphatidylinositol-3 kinase (PI3K)/Akt and estrogen receptor (ER)-ß signaling. METHODS: Human neuroblastoma SK-N-SH cells were pretreated with KRG and subsequently exposed to H2O2. The ability of KRG to inhibit oxidative stress-induced apoptosis was assessed in MTT cytotoxicity assays. Apoptotic protein expression was examined by Western blot analysis. The roles of ER-ß, PI3K, and p-Akt signaling in KRG regulation of apoptosis were studied using small interfering RNAs and/or target antagonists. RESULTS: Pretreating SK-N-SH cells with KRG decreased expression of the proapoptotic proteins p-p53 and caspase-3, but increased expression of the antiapoptotic protein BCL2. KRG pretreatment was also associated with increased ER-ß, PI3K, and p-Akt expression. Conversely, ER-ß inhibition with small interfering RNA or inhibitor treatment increased p-p53 and caspase-3 levels, but decreased BCL2, PI3K, and p-Akt expression. Moreover, inhibition of PI3K/Akt signaling diminished p-p53 and caspase-3 levels, but increased BCL2 expression. CONCLUSION: Collectively, the data indicate that KRG represses oxidative stress-induced apoptosis by enhancing PI3K/Akt signaling via upregulation of ER-ß expression.