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18 pages, 4049 KiB

Open AccessArticle

Natural Compounds Targeting Thymic Stromal Lymphopoietin (TSLP): A Promising Therapeutic Strategy for Atopic Dermatitis

by Muhammad Suleman, Chiara Moltrasio, Paola Maura Tricarico, Angelo Valerio Marzano and Sergio Crovella

Biomolecules 2024, 14(12), 1521; https://doi.org/10.3390/biom14121521 - 27 Nov 2024

Viewed by 734

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease with rising prevalence, marked by eczematous lesions, itching, and a weakened skin barrier often tied to filaggrin gene mutations. This breakdown allows allergen and microbe entry, with thymic stromal lymphopoietin (TSLP) playing a crucial [...] Read more.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with rising prevalence, marked by eczematous lesions, itching, and a weakened skin barrier often tied to filaggrin gene mutations. This breakdown allows allergen and microbe entry, with thymic stromal lymphopoietin (TSLP) playing a crucial role by activating immune pathways that amplify the allergic response. TSLP’s central role in AD pathogenesis makes it a promising therapeutic target. Consequently, in this study, we used the virtual drug screening, molecular dynamics simulation, and binding free energies calculation approaches to explore the African Natural Product Database against the TSLP protein. The molecular screening identified four compounds with high docking scores, namely SA_0090 (−7.37), EA_0131 (−7.10), NA_0018 (−7.03), and WA_0006 (−6.99 kcal/mol). Furthermore, the KD analysis showed a strong binding affinity of these compounds with TSLP, with values of −5.36, −5.36, −5.34, and −5.32 kcal/mol, respectively. Moreover, the strong binding affinity of these compounds was further validated by molecular dynamic simulation analysis, which revealed that the WA_0006-TSLP is the most stable complex with the lowest average RMSD. However, the total binding free energies were −40.5602, −41.0967, −27.3293, and −51.3496 kcal/mol, respectively, showing the strong interaction between the selected compounds and TSLP. Likewise, these compounds showed excellent pharmacokinetics characteristics. In conclusion, this integrative approach provides a foundation for the development of safe and effective treatments for AD, potentially offering relief to millions of patients worldwide. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

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13 pages, 2345 KiB

Open AccessArticle

Comparison of Different Keratinocyte Cell Line Models for Analysis of NLRP1 Inflammasome Activation

by Tian Wang, Amir S. Yazdi and Diana Panayotova-Dimitrova

Biomolecules 2024, 14(11), 1427; https://doi.org/10.3390/biom14111427 - 8 Nov 2024

Viewed by 923

Abstract

The NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome is the most important inflammasome in human keratinocytes. It plays a crucial role in regulating innate immunity in the skin. This study aimed to evaluate NLRP1 inflammasome activation and the corresponding levels of detection [...] Read more.

The NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome is the most important inflammasome in human keratinocytes. It plays a crucial role in regulating innate immunity in the skin. This study aimed to evaluate NLRP1 inflammasome activation and the corresponding levels of detection in different keratinocyte cell lines to identify a suitable in vitro model for analyzing inflammasome activation in keratinocytes. We compared NLRP1 inflammasome activation, expression, and cell death among primary keratinocytes and immortalized keratinocyte cell lines HaCaT, HaSKpw, and SVTERT upon stimulation with ultraviolet B (UVB) irradiation or talabostat. The effects of both NLRP1 inducers on cell death and the modification of NLRP1 molecules were examined using fluorescence-activated cell sorting analysis, Western blotting, and an enzyme-linked immunosorbent assay. The key inflammasome components had varied expression levels among the keratinocyte cell models, with the highest expression observed in primary keratinocytes. Moreover, our data showed that both UVB and talabostat triggered cell death, and NLRP1 inflammasome activation was readily detected in primary keratinocytes but not in the analyzed immortalized keratinocyte cell lines. Therefore, we do not recommend the use of the immortalized keratinocyte cell lines HaCaT, HaSKpw, and SVTERT for analyzing inflammasome activation in keratinocytes; we strongly recommend the use of primary keratinocytes for these studies. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

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7 pages, 207 KiB

Open AccessCommunication

HLA-Cw6 Polymorphism in Autoimmune Blistering Diseases

by Christian Ciolfi, Alvise Sernicola and Mauro Alaibac

Biomolecules 2024, 14(9), 1150; https://doi.org/10.3390/biom14091150 - 12 Sep 2024

Viewed by 994

Abstract

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to [...] Read more.

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

16 pages, 1725 KiB

Open AccessArticle

Novel Fatty Acid Biomarkers in Psoriasis and the Role of Modifiable Factors: Results from the METHAP Clinical Study

by Evangelia Sarandi, Sabine Krueger-Krasagakis, Dimitris Tsoukalas, George Evangelou, Maria Sifaki, Michael Kyriakakis, Efstathia Paramera, Evangelos Papakonstantinou, Gottfried Rudofsky and Aristides Tsatsakis

Biomolecules 2024, 14(9), 1114; https://doi.org/10.3390/biom14091114 - 4 Sep 2024

Viewed by 1359

Abstract

Psoriasis is a chronic, immune-mediated skin condition with significant metabolic complications. Although lipid metabolism is linked to its pathogenesis, reliable biomarkers and the impact of modifiable factors remain underexplored. The aim of the present study was to identify potential biomarkers, study the affected [...] Read more.

Psoriasis is a chronic, immune-mediated skin condition with significant metabolic complications. Although lipid metabolism is linked to its pathogenesis, reliable biomarkers and the impact of modifiable factors remain underexplored. The aim of the present study was to identify potential biomarkers, study the affected metabolic networks, and assess the role of dietary and lifestyle factors in psoriasis. Plasma samples from 56 patients with psoriasis and 49 healthy controls were analyzed, as part of the Metabolic Biomarkers in Hashimoto’s Thyroiditis and Psoriasis (METHAP) clinical trial. Using Gas Chromatography-Mass Spectrometry 23 fatty acids and their ratios were quantified, revealing significant changes in psoriasis. Specifically, lower levels of α-linoleic acid (C18:3n3), linoleic acid (C18:2n6), and gamma-linolenic acid (C18:3n6) were observed along with higher levels of eicosatrienoic acid (C20:3n3), eicosapentaenoic acid (C20:5n3), and erucic acid (C22:1n9). Total polyunsaturated fatty acids (PUFA) were significantly decreased, and the ratio of saturated to total fatty acids (SFA/Total) was increased in psoriasis (p-values < 0.0001). Linear regression identified α-linoleic acid, linoleic acid, eicosatrienoic acid, and eicosapentaenoic acid as potential biomarkers for psoriasis, adjusting for demographic, dietary, and lifestyle confounders. Network analysis revealed key contributors in the metabolic reprogramming of psoriasis. These findings highlight the association between psoriasis and fatty acid biomarkers of inflammation, insulin resistance and micronutrients deficiency, suggesting their potency in disease management. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

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Review

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16 pages, 310 KiB

Open AccessReview

Repurposing Historic Drugs for Neutrophil-Mediated Inflammation in Skin Disorders

by Ludovica Franceschin, Alessia Guidotti, Roberto Mazzetto, Jacopo Tartaglia, Christian Ciolfi, Mauro Alaibac and Alvise Sernicola

Biomolecules 2024, 14(12), 1515; https://doi.org/10.3390/biom14121515 - 27 Nov 2024

Viewed by 1085

Abstract

Neutrophil-mediated inflammation is a key feature of immune-mediated chronic skin disorders, but the mechanistic understanding of neutrophil involvement in these conditions remains incomplete. Dapsone, colchicine, and tetracyclines are established drugs within the dermatologist’s therapeutic armamentarium that are credited with potent anti-neutrophilic effects. Anti-neutrophilic [...] Read more.

Neutrophil-mediated inflammation is a key feature of immune-mediated chronic skin disorders, but the mechanistic understanding of neutrophil involvement in these conditions remains incomplete. Dapsone, colchicine, and tetracyclines are established drugs within the dermatologist’s therapeutic armamentarium that are credited with potent anti-neutrophilic effects. Anti-neutrophilic drugs have established themselves as versatile agents in the treatment of a wide range of dermatological conditions. Some of these agents are approved for the management of specific dermatologic conditions, but most of their current uses are off-label and only supported by isolated reports or case series. Their anti-inflammatory and immunomodulatory properties make them particularly valuable in managing auto-immune bullous diseases, neutrophilic dermatoses, eosinophilic dermatoses, interface dermatitis, and granulomatous diseases that are the focus of this review. By inhibiting inflammatory pathways, reducing cytokine production, and modulating immune responses, they contribute significantly to the treatment and management of these complex skin conditions. Their use continues to evolve as our understanding of these diseases deepens, and they remain a cornerstone of dermatological therapy. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

11 pages, 249 KiB

Open AccessEditor’s ChoiceReview

Schnitzler Syndrome: Insights into Its Pathogenesis, Clinical Manifestations, and Current Management

by Antoine Braud and Dan Lipsker

Biomolecules 2024, 14(6), 646; https://doi.org/10.3390/biom14060646 - 31 May 2024

Cited by 2 | Viewed by 2005

Abstract

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of [...] Read more.

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of interleukin-1 inhibitors demonstrates the key role of this cytokine in the pathogenesis of the disease. However, the physiopathology of Schnitzler syndrome remains elusive, and the main question regarding the relationship between autoinflammatory features and monoclonal gammopathy is still unanswered. The purpose of this narrative review is to describe what is currently known about the pathogenesis of this peculiar disease, as well as to address its diagnosis and management. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

20 pages, 1040 KiB

Open AccessReview

Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis

by Elan May Shellard, Shraddha S. Rane, Stephen Eyre and Richard B. Warren

Biomolecules 2024, 14(5), 548; https://doi.org/10.3390/biom14050548 - 3 May 2024

Cited by 1 | Viewed by 2797

Abstract

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1–3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) [...] Read more.

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1–3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) studies showing that many psoriasis risk genes lie along the IL-23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. This review is focused on the IL-23/Th17 axis, providing an insight into key cell types, cytokines, and intracellular signaling pathways involved. This includes examination of currently available biological treatments, time to relapse post drug withdrawal, and rates of primary/secondary drug failure, showing the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely to reduce the burden of disease for the longest period possible. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

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14 pages, 1009 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Potential of IL-1 Antagonism in Hidradenitis Suppurativa

by Laura Calabrese, Dalma Malvaso, Giulia Coscarella, Flaminia Antonelli, Alessandra D’Amore, Niccolò Gori, Pietro Rubegni, Ketty Peris and Andrea Chiricozzi

Biomolecules 2024, 14(2), 175; https://doi.org/10.3390/biom14020175 - 1 Feb 2024

Cited by 4 | Viewed by 3434

Abstract

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 [...] Read more.

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

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