GRP78 Downregulation in Keratinocytes Promotes Skin Inflammation through the Recruitment and Activation of CCR6+ IL-17A-Producing γδ T Cells.

The migration of γδ T lymphocytes toward skin lesions and their concomitant pathogenic IL-17A production play a crucial role in the pathogenesis of psoriasis. However, the regulatory mechanisms of IL-17A production by γδ T cells and their migration remain to be fully explored. Intracellular GRP78 is a molecular chaperone that regulates endoplasmic reticulum stress, whereas secretory GRP78, as a member of the resolution-associated molecular patterns, exerts immunoregulatory effects. In this study, we reported that both the intracellular GRP78 in skin lesions and secretory GRP78 in the serum were significantly decreased in patients with psoriasis. A GRP78 knockdown exacerbated imiquimod-induced skin inflammation, whereas the application of recombinant GRP78 protein or BIP inducer X (a GRP78 inducer) attenuated the dermatitis. Mechanistically, the GRP78 knockdown in keratinocytes enhanced the production of chemokines, specifically CCL20, which regulates γδ T-cell migration. Moreover, recombinant GRP78 was found to directly bind to γδ T cells to suppress its migration ability and proinflammatory capacities by downregulating the CCR6 and IL-17A expression. Collectively, our results uncovered a pivotal role of GRP78 in the pathogenesis of psoriasis, which was mainly exerted by regulating the interaction between keratinocytes and γδ T cells, and might provide a promising target for psoriasis therapy.

Effects of ambient air pollution on outpatient visits for psoriasis in Wuhan, China: a time-series analysis.

BACKGROUND: Psoriasis can be provoked by both external and internal factors. The effects of environmental factors on psoriasis remain unclear. OBJECTIVES: To investigate the effects of air pollution on outpatient visits for psoriasis. METHODS: A distributed lag nonlinear model following quasi-Poisson regression was used to evaluate the lag effects of air pollutants on psoriasis outpatient visits, adjusting for potential confounders. Stratified analyses were performed to identify potential effect modifications by sex, age and season. RESULTS: In total, 13 536 outpatient visits for psoriasis were recorded in Wuhan, China from 1 January 2015 to 31 December 2019. In the single-pollutant model, exposures to particulate matter (PM) smaller than 2.5 µm (PM2.5), PM smaller than 10 µm (PM10), NO2 and SO2 were found to be significantly associated with increased daily psoriasis outpatient visits. For the largest effects, a 10-µg m-3 increase in concentrations of PM2.5 (lag1), PM10 (lag1), NO2 (lag0) and SO2 (lag3) corresponded to 0.32% [95% confidence interval (CI) 0.01-0.63], 0.26% (95% CI 0.05-0.48), 0.98% (95% CI 0.01-1.96) and 2.73% (95% CI 1.01-4.47) increases in psoriasis outpatient visits, respectively. In the two-pollutant model, only NO2 showed significant and stable effects on the outpatient visits for psoriasis. CONCLUSIONS: Ambient air pollution, especially NO2, appears to be significantly associated with an increased risk of outpatient visits for psoriasis in Wuhan, China. Air pollution control and exposure prevention could be effective measures to relieve the symptoms of psoriasis among these patients.

A Tissue-Tended Mycophenolate-Modified Nanoparticle Alleviates Systemic Lupus Erythematosus in MRL/Lpr Mouse Model Mainly by Promoting Local M2-Like Macrophagocytes Polarization.

Background: Mycophenolate mofetil (MMF), for which the bioactive metabolite is mycophenolic acid (MPA), is a frequently used immunosuppressant for systemic lupus erythematosus (SLE). However, its short half-life and poor biodistribution into cells and tissues hinder its clinical efficacy. Our dextran mycophenolate-based nanoparticles (MPA@Dex-MPA NPs) have greatly improved the pharmacokinetics of MMF/MPA. We here tested the therapeutic efficacy of MPA@Dex-MPA NPs against SLE and investigated the underlying mechanism. Methods: The tissue and immune cell biodistributions of MPA@Dex-MPA NPs were traced using live fluorescence imaging system and flow cytometry, respectively. Serological proinflammatory mediators and kidney damage were detected to assess the efficacy of MPA@Dex-MPA NPs treatments of MRL/lpr lupus-prone mice. Immune cell changes in the kidney and spleen were further analyzed post-treatment via flow cytometry. Bone marrow-derived macrophages were used to investigate the potential mechanism. Results: MPA@Dex-MPA NPs exhibited superior therapeutic efficacy and safety in the MRL/lpr mice using significantly lower administration dosage (one-fifth) and frequency (once/3 days) compared to MMF/MPA used in ordinary practice. The overall prognosis of the mice was improved as they showed lower levels of serological proinflammatory mediators. Moreover, kidney injury was alleviated with reduced pathological signs and decreased urine protein-creatinine ratio. Further investigations of the underlying mechanism revealed a preferential penetration and persistent retention of MPA@Dex-MPA NPs in the spleen and kidney, where they were mostly phagocytosed by macrophages. The macrophages were found to be polarized towards a CD206+ M2-like phenotype, with a downregulation of surface CD80 and CD40, and reduced TNF-α production in the spleen and kidney and in vitro. The expansion of T cells was also significantly inhibited in these two organs. Conclusion: Our research improved the efficacy of MPA for MRL/lpr mice through synthesizing MPA@Dex-MPA NPs to enhance its tissue biodistribution and explored the possible mechanism, providing a promising strategy for SLE therapy.

Polysaccharide mycophenolate-based nanoparticles for enhanced immunosuppression and treatment of immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are characterized by immune dysregulation and severe inflammation caused by the aberrant and overactive host immunological response. Mycophenolic acid (MPA)-based immunosuppressive drugs are potential treatments for IMIDs because of their mild side-effect profile; however, their therapeutic effects are limited by the high albumin binding rate, unsatisfactory pharmacokinetics, and undefined cellular uptake selectivity. Methods: Polysaccharide mycophenolate was synthesized by conjugating MPA molecules to dextran (a typical polysaccharide widely used in drug delivery) and encapsulated extra free MPA molecules to fabricate MPA@Dex-MPA nanoparticles (NPs). The efficacy of these NPs for mediating immunosuppression and treatment of IMIDs was evaluated in imiquimod-induced psoriasis-like skin inflammation in Balb/c mice, a representative IMID model. Results: The MPA@Dex-MPA NPs exhibited high MPA loading efficiency, low albumin binding rates, and sustained MPA release, resulting in improved pharmacokinetics in vivo. Compared to free MPA, MPA@Dex-MPA NPs induced more robust therapeutic effects on IMIDs. Mechanistic studies indicated that MPA@Dex-MPA NPs were primarily distributed in dendritic cells (DCs) and significantly suppressed the overactivated DCs in vivo and in vitro. Furthermore, the recovered DCs rehabilitated the IL-23/Th17 axis function and significantly ameliorated imiquimod-induced psoriasis-like skin inflammation. Importantly, MPA@Dex-MPA NPs showed favorable safety and biocompatibility in vivo. Conclusion: Our results indicated the polysaccharide mycophenolate-based NPs to be highly promising for IMID treatment.

Acitretin-Conjugated Dextran Nanoparticles Ameliorate Psoriasis-like Skin Disease at Low Dosages.

Psoriasis is a common chronic inflammatory skin disease mainly characterized by keratinocyte hyperproliferation and massive infiltration of inflammatory immune cells. Acitretin (ACT), an FDA-approved first-line systemic drug for psoriasis treatment, could suppress the proliferation of keratinocytes and downregulate the expression of inflammatory cytokines by modulating signal transducer and activator of transcription (STAT) signaling pathways. However, dose-dependent side effects of ACT limit its long-term administration in the clinic. Therefore, improving the therapeutic efficacy of ACT to reduce clinical dosage will benefit the patients. Here, we develop ACT-conjugated dextran nanoparticles (ACT-Dex NPs) and evaluated the potential for psoriasis treatment. Our results indicate that ACT-Dex NPs ameliorate psoriasis-like skin disease significantly at a low dosage which does not cause side effects, while neat ACT drugs at an equivalent dosage provide much less benefit. Moreover, we demonstrate that ACT-Dex NPs suppress keratinocyte proliferation more efficiently than neat ACT by enhancing the inhibitory effect on STAT3 phosphorylation. Thus, the proposed ACT-Dex NPs provide an effective and safe option for psoriasis treatment.

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death.

Rationale: The development of a highly effective and tumor-specific therapeutic strategy, which can act against the primary tumor and also condition the host immune system to eliminate distant tumors, remains a clinical challenge. Methods: Herein, we demonstrate a facile yet versatile ZnO-capping and Doxorubicin (DOX)-loaded multifunctional nanocomposite (AuNP@mSiO2@DOX-ZnO) that integrates photothermal properties of gold nanoparticles (NPs), pH-responsive properties and preferential selectivity to tumor cells of ZnO QDs and chemotherapeutic agent into a single NP. The photothermal performance, pH-triggered release and preferential phagocytic ability were assessed. The induced anti-tumor immunity was determined by analyzing immune cell profile in tumor in vivo and molecular mechanism were identified by detecting expression of immunogenic cell death (ICD) markers in vitro. Moreover, mice models of unilateral and bilateral subcutaneous melanoma and lung metastasis were established to evaluate the antitumor effects. Results: As an efficient drug carrier, ZnO-capped NPs guarantee a high DOX payload and an in vitro, efficient release of at pH 5.0. In murine melanoma models, the nanocomposite can significantly inhibit tumor growth for a short period upon low-power laser irradiation. Importantly, ZnO NPs not only demonstrate preferential selectivity for melanoma cells but can also induce ICD. Meanwhile, AuNP@mSiO2-based photothermal therapy (PTT) and DOX are directly cytotoxic towards cancer cells and demonstrate an elevated ICD effect. The induced ICD promotes maturation of dendritic cells, further stimulating the infiltration of effector T cells into tumor sites, preventing tumor growth and distant lung metastases. Conclusions: This study highlights the novel mechanism of ZnO-triggered anti-tumor immunity via inducing ICD. Additionally, we shed light on the multifunctionality of nanocomposites in delivering localized skin tumor therapy as well as inhibiting metastatic growth, which holds great promise in clinical applications.

Hyaluronic Acid-Based Dissolving Microneedle Patch Loaded with Methotrexate for Improved Treatment of Psoriasis.

Methotrexate (MTX) is one of the first-line treatments for moderate to severe psoriasis, while the side effects caused by injection and oral administration of MTX greatly restrict its clinical application. Transdermal drug delivery offers a desirable alternative to the conventional approaches, but the performances of the currently available skin penetration enhancement techniques are not so satisfactory. To address these limitations, we developed a dissolving microneedle (MN) patch made of hyaluronic acid (HA) with excellent water solubility, biocompatibility, biodegradability, and mechanical properties. The amount of MTX encapsulated in the needles of the patch could be controlled during the fabrication process for precise dosage. Interestingly, the MTX-loaded MNs successfully penetrated imiquimod (IMQ)-induced thickened epidermis in mice and delivered the drug intralesionally. Meanwhile, fast dissolution of HA endowed the MNs with operability for patients. We found that the MTX-loaded MNs not only showed well-maintained inhibitory effect in vitro but also alleviated the psoriasis-like skin inflammation in mice. Moreover, the MTX-loaded MNs were significantly more efficacious than taking the same dose of drug orally. Consequently, a higher oral dose of MTX was required for a comparable amelioration, which in turn increased its systemic toxicity. Taken together, the proposed MTX-loaded dissolving MN patch strategy provides a new opportunity for efficient and safe treatment of psoriasis.

5-Aminolevulinic Acid-Loaded Hyaluronic Acid Dissolving Microneedles for Effective Photodynamic Therapy of Superficial Tumors with Enhanced Long-Term Stability.

5-Aminolevulinic acid (5-ALA) is one of the most widely used prodrug in clinical photodynamic therapy of dermatological diseases and cancers; yet, its clinical application is still limited by the shallow skin penetration and unsatisfied stability in any existed formulations. Here, 5-ALA-loaded hyaluronic acid dissolving microneedles (5-ALA@HAMNs) are prepared for photodynamic therapy of superficial tumors. The HAMNs can not only assist the loaded 5-ALA to effectively penetrate the stratum corneum but also provide 5-ALA with an acidic and oxygen-free environment to reduce the dimerization of 5-ALA molecules via Schiff-base bonds and formation of inactive pyrazine derivatives, thus maintaining its chemical structure and biological activity. The chemical stability of 5-ALA in HAMNs is confirmed by UV-vis spectra and mass spectra measurements. The 5-ALA@HAMNs display remarkable tumor elimination both in vitro and in vivo, even after storage at room temperature for nine months, making it a highly potential device for effective delivery of 5-ALA in cancer photodynamic therapy.