Psoriatic Arthritis: Pathogenesis and Targeted Therapies

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4901 - 4901

Published: March 3, 2023

Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. PsA is also associated uveitis bowel (Crohn’s ulcerative colitis). To capture these manifestations as well the comorbidities, to recognize their underlining common pathogenesis, name of psoriatic was coined. The pathogenesis complex multifaceted, an interplay genetic predisposition, triggering environmental factors, activation innate adaptive immune system, although autoinflammation has been implicated. Research identified several immune-inflammatory pathways defined cytokines (IL-23/IL-17, TNF), leading development efficacious therapeutic targets. However, responses drugs occur different tissues involved, resulting challenge global management disease. Therefore, more translational research necessary order identify new targets improve current outcomes. Hopefully, this may become reality through integration omics technologies that allow better understanding relevant cellular molecular players In narrative review, we aim provide updated overview pathophysiology, including latest findings from multiomics studies, describe targeted therapies.

Language: Английский

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The Pharmacological Efficacy of Baicalin in Inflammatory Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9317 - 9317

Published: May 26, 2023

Baicalin is one of the most abundant flavonoids found in dried roots Scutellaria baicalensis Georgi (SBG) belonging to genus Scutellaria. While baicalin demonstrated have anti-inflammatory, antiviral, antitumor, antibacterial, anticonvulsant, antioxidant, hepatoprotective, and neuroprotective effects, its low hydrophilicity lipophilicity limit bioavailability pharmacological functions. Therefore, an in-depth study baicalin’s pharmacokinetics contributes laying theoretical foundation for applied research disease treatment. In this view, physicochemical properties anti-inflammatory activity are summarized terms bioavailability, drug interaction, inflammatory conditions.

Language: Английский

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Depression, a major comorbidity of psoriatic disease, is caused by metabolic inflammation

Journal of the European Academy of Dermatology and Venereology, Journal Year: 2023, Volume and Issue: 37(9), P. 1731 - 1738

Published: May 15, 2023

Psoriatic disease is a chronic, systemic immune-mediated inflammatory disorder comprising three major domains, skin, vascular and bone/joint inflammation. It known for long time that psoriatic associated with number of conditions such as hypertension, dyslipidemia, diabetes (metabolic syndrome) depression. Up to one out five people psoriasis show concomitant In the past, this was attributed psychological stress suffering from chronic condition often visible itchy, leading stigmatization adding significant burden disease. Recent data provide evidence depression linked specific pattern IL-23, IL-17 family cytokines, TNF, IL-6 IL-8 causing neuroinflammation subsequently or depressive behaviour and/or anxiety. shows distinct immune cells (e.g. dendritic cells, Th17 neutrophils), mediators IL-17A/F, TNF) tissue-related factors in all domains different other dermatoses. There striking similarity between leads A risk have been identified disease, most important which are obesity tobacco smoking. Obesity factor anxiety due its signature. Apart psychotherapy anti-depressive medication, targeted treatments psoriasis, including IL-23 inhibitors, can improve depression/depressive symptoms. The review summarizes current knowledge about comorbidity

Language: Английский

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Inflammatory Cytokines in Psoriatic Arthritis: Understanding Pathogenesis and Implications for Treatment

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(14), P. 11662 - 11662

Published: July 19, 2023

Psoriatic arthritis (PsA) is a persistent, inflammatory disease that affects individuals with psoriasis, arthritis, and enthesitis. Research has demonstrated cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-23 (IL-23), interleukin-17 (IL-17) play pivotal role in both the onset progression of PsA. These are generated by activated immune cells stimulate attraction to synovium joint tissues, resulting deterioration cartilage bone. The blocking these become successful treatment strategy for PsA, biological drugs inhibit TNF-α, IL-23, IL-17 have notable clinical benefits. association between PsA other types or chemokines, excluding IL-17, been extensively investigated numerous studies. findings may provide chance discovery novel therapeutic agents targeting molecules, distinct from currently approved biologics targeted synthetic disease-modifying anti-rheumatic drugs. In this review, we discuss current understanding pathogenesis implications treatment.

Language: Английский

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Dual targeting of mTOR/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 18, 2023

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to cytokine production, psoriasis associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte migration, keratinocytes proliferation upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating humans variable results necessitating improved therapies. Fisetin, natural dietary polyphenol anti-oxidant anti-proliferative properties, covalently binds mTOR/S6K1. The effects fisetin on its underlying mechanisms not clearly defined. Here, we evaluated immunomodulatory Th1/Th17-cytokine-activated adult human (HEKa) anti-CD3/CD28-stimulated CD4 + T cells compared these activities those rapamycin (an mTOR inhibitor). Transcriptomic analysis HEKa revealed 12,713 differentially expressed genes (DEGs) fisetin-treated group 7,374 DEGs rapamycin-treated group, both individually treated group. Gene ontology enriched functional groups related PI3K/Akt/mTOR signaling pathways, psoriasis, development. Using silico molecular modeling, observed high binding affinity IL-17A. vitro , significantly inhibited activity, increased expression autophagy markers LC3A/B Atg5 suppressed secretion IL-17A activated lymphocytes co-cultured HEKa. Topical administration an imiquimod (IMQ)-induced mouse model exhibited better effect than reducing psoriasis-like inflammation phosphorylation promoting keratinocyte differentiation mice Fisetin also T-lymphocytes F4/80 macrophage infiltration into skin. We conclude potently inhibits pathway promotes alleviate IMQ-induced disease mice. Altogether, our findings suggest as potential treatment possibly other diseases.

Language: Английский

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Redox Pathogenesis in Rheumatic Diseases

ACR Open Rheumatology, Journal Year: 2024, Volume and Issue: 6(6), P. 334 - 346

Published: April 25, 2024

Despite being some of the most anecdotally well-known roads to pathogenesis, mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation cellular immune system and characteristic development autoantibodies have been linked oxidative stress. Typical clinical manifestations, such as joint swelling deformities inflammation skin internal organs, also connected directly or indirectly redox mechanisms. differences in generation restraint stress provide compelling evidence for broad variety pathology among explain common triggers discordant manifestations these diseases. Growing pathogenesis has provided a array new potential therapeutic targets. Here, we explore by which is generated, its roles autoimmunity end-organ damage, discuss how individual exhibit unique features that offer targets interventions.

Language: Английский

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Dynamics of inflammation-associated plasma proteins following faecal microbiota transplantation in patients with psoriatic arthritis and healthy controls: exploratory findings from the FLORA trial

RMD Open, Journal Year: 2024, Volume and Issue: 10(1), P. e003750 - e003750

Published: Jan. 1, 2024

Objectives The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins. Methods This study relates FLORA trial cohort, where 31 moderate-to-high peripheral PsA disease activity, despite at least 3 months methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants allocated receive either one gastroscopic-guided healthy donor FMT (n=15) or (n=16). Patient samples collected baseline, week 4, 12 26 while from age-matched sex-matched controls (HC) baseline. Samples analysed using proximity extension assay technology (Olink Target-96 Inflammation panel). Results Levels proteins differed significantly between HC pre-FMT (adjusted p<0.05), which 10 elevated PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, IL-2. group, levels changed across all timepoints (tumour necrosis factor (TNF), IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences sham-treated observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell (p=0.024), matrix metalloproteinase-1 (p=0.038), SLAMF1 (p=0.042). had largest positive effect Axin-1 CCL25 negative CCL19 IL-6. Conclusions Patients active have distinct immunological signature compared pre-FMT. affects several these markers, including sustained elevation IFN-γ. Trial registration number NCT03058900 .

Language: Английский

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Gasdermin E-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation

British Journal of Dermatology, Journal Year: 2024, Volume and Issue: 191(3), P. 385 - 396

Published: April 23, 2024

Psoriasis is a common chronic inflammatory disease with an unclear aetiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce cell death.

Language: Английский

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Psoriasis as a systemic disease

Deutsches Ärzteblatt international, Journal Year: 2024, Volume and Issue: unknown

Published: July 4, 2024

Psoriasis was long regarded as an inflammatory disease limited to the skin. Data from dermatologic, rheumatologic and cardiologic research now show it be a systemic disease, for which term psoriatic is used.

Language: Английский

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Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 12, 2025

IL-23 is implicated in the pathogenesis of immune-mediated inflammatory diseases, and myeloid cells that express Fc gamma receptor 1 (FcγRI or CD64) on their surface have been recently identified as a primary source inflamed tissue. Our complementary analyses transcriptomic datasets from psoriasis IBD showed increased expression CD64 transcripts tissue, greater abundance cell types with co-expression IL-23. These findings led us to explore potential implications binding function IL-23–targeting monoclonal antibodies (mAbs). Guselkumab risankizumab are mAbs target IL-23p19 subunit. has native domain while contains mutations diminish FcγRs. In flow cytometry assays, guselkumab, but not risankizumab, Fc-mediated IFNγ-primed monocytes. bound IL-23–producing monocytes simultaneously captured secreted these cells. did induce cytokine production. live-cell confocal imaging + macrophages, mediated internalization low-pH intracellular compartments. demonstrated similar potency for inhibition signaling cellular assays exogenous addition However, co-culture THP-1 an IL-23–responsive reporter line, guselkumab Fc-dependent enhanced compared inhibiting signaling. vitro data highlight tissue contribute potent neutralization at its source.

Language: Английский

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