Single-Cell RNA Sequencing Identifies WARS1+ Mesenchymal Stem Cells with Enhanced Immunomodulatory Capacity and Improved Therapeutic Efficacy.

Psoriasis is a common inflammatory skin disorder with no cure. Mesenchymal stem cells (MSCs) have immunomodulatory properties for psoriasis, but the therapeutic efficacies varied, and the molecular mechanisms were unknown. In this study, we improved the efficacy by enhancing the immunomodulatory effects of umbilical cord-derived MSCs (UC-MSCs). UC-MSCs stimulated by TNF-α and IFN-γ exhibited a better therapeutic effect in a mouse model of psoriasis. Single-cell RNA sequencing revealed that the stimulated UC-MSCs overrepresented a subpopulation expressing high tryptophanyl-tRNA synthetase 1 (WARS1). WARS1-overexpressed UC-MSCs treat psoriasis-like skin inflammation more efficiently than control UC-MSCs by restraining the proinflammatory macrophages. Mechanistically, WARS1 maintained a RhoA-Akt axis and governed the immunomodulatory properties of UC-MSCs. Together, we identify WARS1 as a master regulator of UC-MSCs with enhanced immunomodulatory capacities, which paves the way for the directed modification of UC-MSCs for escalated therapeutic efficacy.

Migration and distribution characteristics of typical organic pollutants in condensable particulate matter of coal-fired flue gas and by-products of wet flue gas desulfurization system.

The wet flue gas desulfurization (WFGD) system of coal-fired power plants shows a good removal effect on condensable particulate matter (CPM), reducing the dust removal pressure for the downstream flue gas purification devices. In this work, the removal effect of a WFGD system on CPM and its organic pollutants from a coal-fired power plant was studied. By analyzing the organic components of the by-products emitted from the desulfurization tower, the migration characteristics of organic pollutants in gas, liquid, and solid phases, as well as the impact of desulfurization towers on organic pollutants in CPM, were discussed. Results show that more CPM in the flue gas was generated by coal-fired units at ultra-low load, and the WFGD system had a removal efficiency nearly 8% higher than that at full load. The WFGD system had significant removal effect on two typical esters, especially phthalate esters (PAEs), with the highest removal efficiency of 49.56%. In addition, the WFGD system was better at removing these two esters when the unit was operating at full load. However, it had a negative effect on n-alkanes, which increased the concentration of n-alkanes by 8.91 to 19.72%. Furthermore, it is concluded that the concentration distribution of the same type of organic pollutants in desulfurization wastewater was similar to that in desulfurization slurry, but quite different from that in coal-fired flue gas. The exchange of three organic pollutants between flue gas and desulfurization slurry was not significant, while the concentration distribution of organic matters in gypsum was affected by coal-fired flue gas.

Identification and pre-clinical investigation of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid as a drug for external use to treat psoriasis.

BACKGROUND AND PURPOSE: Psoriasis vulgaris is a refractory skin inflammatory disorder with 80% of the cases belonging to the mild-to-moderate type, which can be controlled by topical treatment. Nevertheless, the drugs for external use have not been upgraded for decades. We modified acetyl-11-keto-beta-boswellic acid (ABKA), a natural compound shown to treat psoriasis animal models, to improve efficacy and solubility for topical use. EXPERIMENTAL APPROACH: Eleven compounds were synthesized using AKBA as a lead compound, and their effects on Th17 cell differentiation were screened. 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA) potently inhibited Th17 cell differentiation. Its efficacy in a mouse model of psoriasis was assessed along with its pharmacology and safety profile when topically or systemically delivered to several animal species. KEY RESULTS: CKBA inhibited mouse and human Th17 cell differentiation with an IC50 of 3.28 and 3.61 µM, respectively, and directly targeted acetyl-CoA carboxylase 1 (ACC1). Safety evaluation and toxicity tests suggested that systemically delivered high-dose CKBA for 14 days had no dose-associated adverse effects on the CNS, haematopoietic, cardiovascular, respiratory and digestive systems of cynomolgus monkeys. CKBA ointment permeated the skin and did not irritate or sensitize intact skin. CKBA ointment mediated dose-dependent suppression of imiquimod-induced psoriasis-like skin inflammation with slow absorption and limited bioavailability (<10% in rats and <1% in minipigs). CONCLUSIONS AND IMPLICATIONS: CKBA is safe when topically or systemically delivered to animals. The beneficial effects of CKBA ointment in a mouse model of psoriasis indicate that this is a promising drug candidate for further development as a treatment for psoriasis.

CKBA suppresses mast cell activation via ERK signaling pathway in murine atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)-induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA-seq analysis revealed that CKBA downregulated the extracellular signal-regulated kinase (ERK) signaling in BM-derived mast cells activated by anti-2,4-dinitrophenol/2,4-dinitrophenol-human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t-butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD.

The effect of air pollution control devices in coal-fired power plants on the removal of condensable and filterable particulate matter.

Total particulate matter (TPM), including condensable and filterable particulate matter (CPM and FPM), is one of the pollutants that need to be controlled in the coal combustion process. In this study, CPM and FPM were sampled from sixteen coal-fired power units and two coal-fired industrial units. The removal effects of air pollution control devices equipped in the units on the migration and emission of particles were investigated by analyzing samples from inlets and outlets of apparatus. The average removal efficiency of TPM by dry-type dust removal equipment, wet flue gas desulfurization devices, and wet-type precipitators reached 98.57 ± 0.90%, 44.89 ± 15.01%, and 28.45 ± 7.78%, respectively. The removal efficiency of dry-type dust removal equipment and wet-type precipitators to TPM is mainly determined by the purification effect of FPM and CPM, respectively, and both types of particles contribute to the removal efficiency of desulfurization systems to total TPM. The concentrations of CPM (12.01 ± 5.64 mg/Nm3) and FPM (1.95 ± 0.86 mg/Nm3) emitted from ultra-low emission units were the lowest, and CPM is the dominant particle, especially the higher proportion of organic components in CPM.

Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis.

Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc+ papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research.

Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis.

Protein Phosphatase 6 down-regulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis, indicating that restoration of protein phosphatase 6 can be a rational strategy for psoriasis treatment. Through the phenotypic screen, we here identify L-menthol that ameliorates psoriasis-like skin inflammation by increasing protein phosphatase 6 in keratinocytes. Target identification approaches reveal an indispensable role for the transcription factor hairy and enhancer of split 1 in governing the protein phosphatase 6-upregulating function of L-menthol in keratinocytes. The transcription factor hairy and enhancer of split 1 is diminished in the epidermis of psoriasis patients and imiquimod-induced mouse model, while L-menthol upregulates the transcription factor hairy and enhancer of split 1 by preventing its proteasomal degradation. Mechanistically, the transcription factor hairy and enhancer of split 1 transcriptionally activates the expression of immunoglobulin-binding protein 1 which promotes protein phosphatase 6 expression and inhibits its ubiquitination. Collectively, we discover a therapeutic compound, L-menthol, for psoriasis, and uncover the dysfunctional the transcription factor hairy and enhancer of split 1- immunoglobulin-binding protein 1- protein phosphatase 6 axis that contributes to psoriasis pathology by using L-menthol as a probe.

A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting Treg differentiation.

Recent evidence has revealed that small polypeptides (containing fewer than 100 amino acids) can be translated from noncoding RNAs (ncRNAs), which are usually defined as RNA molecules that do not encode proteins. However, studies on functional products translated from primary transcripts of microRNA (pri-miRNA) are quite limited. Here, we describe a peptide termed miPEP31 that is encoded by pri-miRNA-31. miPEP31 is highly expressed in Foxp3+ regulatory T cells (Tregs ) and significantly promotes the differentiation of Tregs without affecting their inhibitory ability. Our results show that miPEP31 is a cell-penetrating peptide both in vitro and in vivo. miPEP31 downregulates miR-31 expression, enhances peripheral Treg induction, and dramatically suppresses experimental autoimmune encephalomyelitis. Mechanistically, we show that miPEP31 acts as a transcriptional repressor inhibiting the expression of miRNA-31, a negative regulator of Tregs . Our results reveal an indispensable role of miPEP31 in maintaining immune homeostasis by promoting Treg differentiation and also present a potential therapeutic peptide for modulating miRNA expression and treating autoimmune diseases.

Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity.

Regulatory T (Treg) cells constitute a dynamic population that is critical in autoimmunity. Treg cell therapies for autoimmune diseases are mainly focused on enhancing their suppressive activities. However, recent studies demonstrated that certain inflammatory conditions induce Treg cell instability with diminished FoxP3 expression and convert them into pathogenic effector cells. Therefore, the identification of novel targets crucial to both Treg cell function and plasticity is of vital importance to the development of therapeutic approaches in autoimmunity. In this study, we found that conditional Pp6 knockout (cKO) in Treg cells led to spontaneous autoinflammation, immune cell activation, and diminished levels of FoxP3 in CD4+ T cells in mice. Loss of Pp6 in Treg cells exacerbated two classical mouse models of Treg-related autoinflammation. Mechanistically, Pp6 deficiency increased CpG motif methylation of the FoxP3 locus by dephosphorylating Dnmt1 and enhancing Akt phosphorylation at Ser473/Thr308, leading to impaired FoxP3 expression in Treg cells. In summary, our study proposes Pp6 as a critical positive regulator of FoxP3 that acts by decreasing DNA methylation of the FoxP3 gene enhancer and inhibiting Akt signaling, thus maintaining Treg cell stability and preventing autoimmune diseases.

Study on characteristics of organic components in condensable particulate matter before and after wet flue gas desulfurization system of coal-fired power plants.

Wet flue gas desulfurization (WFGD) in coal-fired power plants has a great impact on the emission of particulate matter, including filterable particulate matter (FPM) and condensable particulate matter (CPM). In this paper, CPM and FPM in flue gas before and after WFGD in coal-fired power plants were sampled in parallel. FPM was tested according to ISO standard 23210-2009, and CPM was tested according to U.S. EPA Method 202. A method for quantitatively analyzing fatty acid methyl esters in CPM was established, and the removal capacity of fatty acid methyl esters and phthalate esters by WFGD in a typical coal-fired unit was compared. Results show that WFGD has a significant effect on particle size distribution, concentration, and chemical composition. WFGD has a high removal efficiency of inorganic components in CPM, up to 54.74%. CPM contains a variety of organic compounds, including hydrocarbons, esters, siloxanes, halogenated hydrocarbons, and so on. In particular, esters are an important component in CPM, whose concentration tends to decrease after WFGD. Furthermore, a total of 11 fatty acid methyl esters and 5 phthalate esters were detected in CPM before and after WFGD. Noted that fatty acid methyl esters account for 13.38% of CPM, which make a higher contribution to the concentration of particulate matter than phthalate esters, while WFGD has a stronger control effect on the removal of phthalates.

Emission characteristics of PM2.5 and components of condensable particulate matter from coal-fired industrial plants.

Particulate matter (PM), including condensable particulate matter (CPM) and filterable particulate matter (FPM), emitted from coal combustion is one of the major contributors to air pollution. In this study, CPM and FPM were sampled from two coal-fired industrial boilers with air pollution control devices (APCDs). The emission concentration of total PM (CPM and FPM) and inorganic components of CPM were studied. The organic fractions in CPM and raw coal were analyzed using a gas chromatograph/mass spectrometer (GC/MS). The concentrations of total PM in the flue gas decreased from 1475.61 to 7.68 mg/Nm3 in unit 1, and from 2451.62 to 29.38 mg/Nm3 in unit 2 after the flue gas passed through the APCDs. CPM accounted for 51.42-91.93% of total PM emitted from stacks, of which organic components (73.87-96.30%) were one of the main constituents. Although aromatic hydrocarbons are one of the major components of raw coal, they were almost nonexistent in the CPM emitted from coal combustion. Saturated hydrocarbons accounted for the largest proportion of organic components in CPM, 49.19% in unit 1 and 61.16% in unit 2. The proportion of esters in the oxygen-containing derivatives of CPM emitted from two units was relatively high. SO42- was the inorganic component with the largest concentration in CPM emitted from the boiler units. This study will improve the understanding of the emissions levels of PM2.5 and the properties of CPM that originate from the coal-fired industrial processes.

SZB120 Exhibits Immunomodulatory Effects by Targeting eIF2α to Suppress Th17 Cell Differentiation.

IL-17-secreting Th17 cells play an important role in the pathogenesis of various inflammatory and autoimmune diseases. IL-17-targeted biologics and small molecules are becoming promising treatments for these diseases. In this study, we report that SZB120, a derivative of the natural compound 3-acetyl-ß-boswellic acid, inhibits murine Th17 cell differentiation by interacting with the α-subunit of eukaryotic initiation factor 2 (eIF2α). We showed that SZB120 directly interacts with eIF2α and contributes to serine 51 phosphorylation of eIF2α. The suppressive effect of SZB120 on Th17 cell differentiation was reversed by GSK2606414, an inhibitor of eIF2α phosphokinase. Phosphorylation of eIF2α induced by SZB120 decreased the protein expression of IκBζ, which is important for Th17 cell differentiation. Notably, interaction with eIF2α by SZB120 also impaired glucose uptake and glycolysis in T cells. In vivo, SZB120 treatment of C57BL/6 mice significantly attenuated IL-17/Th17-mediated autoimmune disease. Our study indicates that SZB120 is a promising drug candidate for IL-17/Th17-mediated inflammatory diseases.

A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation.

Many annotated long noncoding RNAs (lncRNAs) harbor predicted short open reading frames (sORFs), but the coding capacities of these sORFs and the functions of the resulting micropeptides remain elusive. Here, we report that human lncRNA MIR155HG encodes a 17-amino acid micropeptide, which we termed miPEP155 (P155). MIR155HG is highly expressed by inflamed antigen-presenting cells, leading to the discovery that P155 interacts with the adenosine 5'-triphosphate binding domain of heat shock cognate protein 70 (HSC70), a chaperone required for antigen trafficking and presentation in dendritic cells (DCs). P155 modulates major histocompatibility complex class II-mediated antigen presentation and T cell priming by disrupting the HSC70-HSP90 machinery. Exogenously injected P155 improves two classical mouse models of DC-driven auto inflammation. Collectively, we demonstrate the endogenous existence of a micropeptide encoded by a transcript annotated as "non-protein coding" and characterize a micropeptide as a regulator of antigen presentation and a suppressor of inflammatory diseases.

Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis.

Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-ß and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis.

Calcium Homeostasis: A Potential Vicious Cycle of Bone Metastasis in Breast Cancers.

Cancers have been considered as one of the most severe health problems in the world. Efforts to elucidate the cancer progression reveal the importance of bone metastasis for tumor malignancy, one of the leading causes for high mortality rate. Multiple cancers develop bone metastasis, from which breast cancers exhibit the highest rate and have been well-recognized. Numerous cells and environmental factors have been believed to synergistically facilitate bone metastasis in breast cancers, from which breast cancer cells, osteoclasts, osteoblasts, and their produced cytokines have been well-recognized to form a vicious cycle that aggravates tumor malignancy. Except the cytokines or chemokines, calcium ions are another element largely released from bones during bone metastasis that leads to hypercalcemia, however, have not been well-characterized yet in modulation of bone metastasis. Calcium ions act as a type of unique second messenger that exhibits omnipotent functions in numerous cells, including tumor cells, osteoclasts, and osteoblasts. Calcium ions cannot be produced in the cells and are dynamically fluxed among extracellular calcium pools, intracellular calcium storages and cytosolic calcium signals, namely calcium homeostasis, raising a possibility that calcium ions released from bone during bone metastasis would further enhance bone metastasis and aggravate tumor progression via the vicious cycle due to abnormal calcium homeostasis in breast cancer cells, osteoclasts and osteoblasts. TRPs, VGCCs, SOCE, and P2Xs are four major calcium channels/routes mediating extracellular calcium entry and affect calcium homeostasis. Here we will summarize the overall functions of these four calcium channels in breast cancer cells, osteoclasts and osteoblasts, providing evidence of calcium homeostasis as a vicious cycle in modulation of bone metastasis in breast cancers.

Melanoma suppression by quercein is correlated with RIG-I and type I interferon signaling.

Melanoma is a life-threatening cancer with limited treatments. Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor (PRR) crucial to RNA virus sensing, interferon production, and tumor suppression. Quercetin, a natural flavonoid, has particularly therapeutic interests to prevent and treat cancer, for its pharmacological effects against oxidant, inflammation, and angiogenesis. Quercetin was investigated for its anti-melanoma activity and potential mechanisms in this study. We found that quercetin inhibited mouse melanoma growth in vivo, and suppressed proliferation and promoted apoptosis of both B16 and A375 cells in vitro. Quercetin upregulated IFN-α and IFN-ß expression through activating RIG-I promoter in B16 cells. The induction of IFN-α and IFN-ß, which could be severely impaired by silencing RIG-I induced interferon stimulated genes (ISGs). Moreover, RIG-I likely amplifies antitumor effects by activating signal transduction and activator of transcription 1 (STAT1) in the IFN-JAK-STAT pathway in an autocrine and paracrine manner. Our study provided novel insights regarding biological and anti-proliferative activities of quercetin against melanoma, and we identified RIG-I as a potential target in anti-tumor therapies.

Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease which lacks effective strategies for the treatment. Natural compounds with biological activities are good tools to identify new targets with therapeutic potentials. Acetyl-11-keto-ß-boswellic acid (AKBA) is the most bioactive ingredient of boswellic acids, a group of compounds with anti-inflammatory and anti-cancer properties. Target identification of AKBA and metabolomics analysis of psoriasis helped to elucidate the molecular mechanism underlying its effect, and provide new target(s) to treat the disease. METHODS: To explore the targets and molecular mechanism of AKBA, we performed affinity purification, metabolomics analysis of HaCaT cells treated with AKBA, and epidermis of imiquimod (IMQ) induced mouse model of psoriasis and psoriasis patients. FINDINGS: AKBA directly interacts with methionine adenosyltransferase 2A (MAT2A), inhibited its enzyme activity, decreased level of S-adenosylmethionine (SAM) and SAM/SAH ratio, and reprogrammed one­carbon metabolism in HaCaT cells. Untargeted metabolomics of epidermis showed one­carbon metabolism was activated in psoriasis patients. Topical use of AKBA improved inflammatory phenotype of IMQ induced psoriasis-like mouse model. Molecular docking and site-directed mutagenesis revealed AKBA bound to an allosteric site at the interface of MAT2A dimer. INTERPRETATION: Our study extends the molecular mechanism of AKBA by revealing a new interacting protein MAT2A. And this leads us to find out the dysregulated one­carbon metabolism in psoriasis, which indicates the therapeutic potential of AKBA in psoriasis. FUND: The National Natural Science Foundation, the National Program on Key Basic Research Project, the Shanghai Municipal Commission, the Leading Academic Discipline Project of the Shanghai Municipal Education Commission.

Increased circulating follicular regulatory T cells in Hashimoto's thyroiditis.

OBJECTIVE: Follicular T helper (Tfh) cells are involved in the pathogenesis of Hashimoto's thyroiditis (HT), while follicular T regulatory (Tfr) cells inhibit Tfh cells, which mediate B cell responses. However, the role of Tfr cells in HT remains unclear. METHODS: Forty-six healthy controls (HCs) and 84 HT patients were enrolled in the study. The percentage of Treg cells, CXCR5- Treg cells, and Tfr cells; the Tfr/Tfh ratio; and the percentage of ICOS, PD-1, CTLA-4, CXCR3 and CCR6 in Tfr cells were investigated; furthermore, the associations between the percentage of Tfr cells or the Tfr/Tfh ratio and the autoantibody indices were investigated. RESULTS: Compared with that in the HCs, the percentage of Treg cells in the HT patients was not significantly changed, but the percentage of CXCR5- Tfr cells was decreased. In contrast, both the percentage of Tfr cells and the Tfr/Tfh ratio were significantly increased in the HT patients. Among the Tfr cells, the percentage of Th2-like Tfr cells was increased in the HT patients, while the percentage of Th17-like Tfr cells was decreased. Moreover, the percentages of ICOS and PD-1 on Tfr cells were significantly increased in the HT patients, while the percentage of CTLA-4 on Tfr cells was significantly decreased. However, the percentage of ICOS, PD-1 and CTLA-4 on Treg or CXCR5- Treg cells was not significantly changed. Last, no association was found between either the percentage of Tfr cells or the Tfr/Tfh ratio and the antithyroglobulin and antithyroid peroxidase antibody levels in the HT patients. CONCLUSIONS: In the HT patients, the circulating Tfr cell percentage and Tfr/Tfh ratio were significantly increased, but the humoral immune function of Tfr cells might be impaired.

RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.

Retinoic acid inducible-gene I (RIG-I) functions as one of the major sensors of RNA viruses. DDX58, which encodes the RIG-I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG-I by 5'ppp-dsRNA, its synthetic ligand, directly causes the production of IL-23 and triggers psoriasis-like skin disease in mice. Repeated injections of IL-23 to the ears failed to induce IL-23 production and a full psoriasis-like skin phenotype, in either germ-free or RIG-I-deficient mice. RIG-I is also critical for a full development of skin inflammation in imiquimod (IMQ)-induced psoriasis-like mouse model. Furthermore, RIG-I-mediated endogenous IL-23 production was mainly confined to the CD11c+ dendritic cells (DCs) via nuclear factor-kappa B (NF-κB) signaling, and stimulated RIG-I expression in an auto-regulatory feedback loop. Thus, our data suggest that the dysregulation in the antiviral immune responses of hosts through the innate pattern recognition receptors may trigger the skin inflammatory conditions in the pathophysiology of psoriasis.

M2 macrophages contribute to osteogenesis and angiogenesis on nanotubular TiO2 surfaces.

The monocyte/macrophage system plays an essential role in the host response and the fate of endosseous implanted materials. Macrophage behavior was thought to be regulated by nanostructured titanium which has been considered as a very promising candidate for dental implants. However, there is little known for subsequent effects of these activated macrophages on osteogenesis and angiogenesis which were essential for bone integration. Here we presented two different dimensions of titanium nanotubes generated by anodic oxidation at 10 V (NT 10) and 20 V (NT 20), respectively. The behavior of macrophages on the surfaces was evaluated, and their conditioned medium (CM) was collected to stimulate MC3T3 and HUVECs, with commercially pure titanium (cp Ti) as control. We found that NT 20 induced macrophage activation similar to the anti-inflammatory M2 macrophage state with the enhanced expression of IL-10 and ARG, while NT 10 was associated with M1 macrophage phenotype characterized by high levels of IL-1ß, iNOS and TNF-α. Furthermore, the osteogenic capacity of MC3T3 in CM from NT 20 was enhanced (NT 20 > NT 10 ≈ cp Ti) and the tube formation capacity of HUVECs was promoted in CM from nanotubular surfaces with increasing tube dimensions (NT 20 > NT 10 > cp Ti). Our data suggest that dental implants with the large nanotube dimension surface could result in a favorable osteoimmunomodulatory microenvironment for the establishment of osseointegration.