Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway.

Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.

m6A RNA methylation: The latent string-puller in fibrosis.

Fibrosis is a pathological phenomenon characterized by the aberrant accumulation of extracellular matrix (ECM) in tissues. Fibrosis is a universally age-related disease involving that many organs and is the final stage of many chronic inflammatory diseases, which often threaten the patient's health. Undoubtedly, fibrosis has become a serious economic and health burden worldwide, However, the pathogenesis of fibrosis is complex. Further, the key molecules still remain to be unraveled. Hence, so far, there have been no effective treatments designed against the key targets of fibrosis. The methylation modification on the nitrogen atom at position 6 of adenine (m6A) is the most common mRNA modification in mammals. There is increasing evidence that m6A is actively involved in the pathogenesis of fibrosis. This review aims to highlight m6A-associated mechanisms and functions in several organic fibrosis, which implies that m6A is universal and critical for fibrosis and summarize the outlook of m6A in the treatment of fibrosis. This may light up the unknown aspects of this condition for researchers interested to explore fibrosis further.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1ß (IL-1ß) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1ß and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis.

Objectives: Systemic sclerosis (SSc) is an autoimmune disease caused by various pathogenic factors, including hypoxia. Hypoxia stimulates the production of the extracellular matrix to promote fibrosis. However, the integrated function and the underlying mechanism of hypoxia in SSc are unclear. Methods: In the present study, we used Agilent SurePrint G3 Human Gene Expression v3 for the transcriptional sequencing of fibroblasts with and without hypoxia to detect differentially expressed genes (DEGs) in hypoxia. We analyzed the results with the transcriptome data of SSc lesions (GSE95065) to select the co-DEGs. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on the basis of the co-DEGs using the R package ClusterProfiler, which showed that hypoxia and cross talk of hypoxia with other pathogenic factors are involved in the pathogenesis of SSc. Furthermore, we constructed a protein-protein interaction (PPI) network of co-DEGs and screened two significant functional expression modules. Results: We identified nine hub genes (ALDH1A1, EGF, NOX4, LYN, DNTT, PTGS2, TKT, ACAA2, and ALDH3A1). These genes affect the pentose phosphate pathway, oxidative stress, and lipolysis. Conclusion: Our study provides insights into the mechanisms underlying the effects of hypoxia on SSc pathogenesis, which will help to better understand SSc pathogenesis and develop new therapeutic strategies for SSc.

Overexpression of OASL upregulates TET1 to induce aberrant activation of CD4+ T cells in systemic sclerosis via IRF1 signaling.

BACKGROUND: Systemic sclerosis (SSc), an autoimmune disease with unknown etiology and pathogenesis, is characterized by abnormal autoimmunity, vascular dysfunction, and progressive fibrosis of skin and organs. Studies have shown that a key factor in the pathogenesis of SSc is aberrant activation of CD4+ T cells. Our previous studies have shown that a global hypomethylation state of CD4+ T cells is closely related to aberrant activation. However, the exact mechanism of hypomethylation in CD4+T cells is not yet clear. METHODS: Illumina HiSeq 2500 Platform was used to screen differentially expressed genes and explore the role of OASL, TET1, and IRF1 in the abnormal activation of CD4+T cells in SSc. Finally, double luciferase reporter gene experiments were used to analyze the interaction between IRF1 and TET1. RESULTS: OASL overexpression could upregulate TET1 to increase the hydroxymethylation levels of CD4+ T cells and induce high expression of functional proteins (CD40L and CD70), thus promoting CD4+T cell aberrant activation. Moreover, OASL upregulated TET1 via IRF1 signaling activation, and a double luciferase reporter gene experiment revealed that IRF1 can bind to the TET1 promoter region to regulate its expression. CONCLUSIONS: OASL participates in the regulation of abnormal hypomethylation of CD4+ T cells in SSc, which implies a pivotal role for IFN signaling in the pathogenesis of SSc. Regulating DNA methylation and IFN signaling may serve as therapeutic treatments in SSc.

Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling.

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-ß/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

Nonsense Suppression Therapy: An Emerging Treatment for Hereditary Skin Diseases.

Nonsense mutations cause the premature termination of protein translation via premature termination codons (PTCs), leading to the synthesis of incomplete functional proteins and causing large numbers of genetic disorders. The emergence of nonsense suppression therapy is considered to be an effective method for the treatment of hereditary diseases, but its application in hereditary skin diseases is relatively limited. This review summarizes the current research status of nonsense suppression therapy for hereditary skin diseases, and discusses the potential opportunities and challenges of applying new technologies related to nonsense suppression therapy to dermatology. Further research is needed into the possible use of nonsense suppression therapy as a strategy for the safer and specific treatment of hereditary skin diseases.

Efficacy of mycophenolate mofetil versus cyclophosphamide in systemic sclerosis-related interstitial lung disease: a systematic review and meta-analysis.

OBJECTIVE: This study systematically compares the efficacy and adverse events of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: The EMBASE and PubMed databases were systematically searched to find all relevant studies. Quality assessment, study selection, and data extraction were independently conducted by two reviewers. The mean changes in forced vital capacity (FVC)% and diffusing capacity for carbon monoxide (DLco)% of the patients were selected to be primary outcome measures. Stata software was used for the pooled analysis. RESULTS: Among 284 titles screened from multiple databases, six studies met the inclusion criteria (one randomized controlled trial, three prospective observational studies, and two retrospective observational studies). The summary weighted mean difference (WMD) of FVC change in the MMF group compared with the CYC group was - 1.17 (95% CI: - 2.713, 0.373; P = 0.137), and the summary WMD of DLco change in the MMF group compared with the CYC group was 2.245 (95% CI: 0.258, 4.232; P = 0.027). Studies enrolled showed that adverse events were less common in the MMF group. CONCLUSIONS: The efficacy of MMF with respect to FVC and DLco improvement is comparable to that of CYC, and MMF is preferred on the basis of the occurrence of adverse events. Key Points • A systematic review and meta-analysis was conducted to compare the efficacy and adverse events of mycophenolate mofetil and cyclophosphamide in patients with systemic sclerosis-related interstitial lung disease. • The efficacy of MMF with respect to FVC and DLco improvement is comparable to that of CYC, and MMF is preferred on the basis of the occurrence of adverse events.

A comparison and review of three sets of classification criteria for systemic lupus erythematosus for distinguishing systemic lupus erythematosus from pure mucocutaneous manifestations in the lupus disease spectrum.

Although the original purpose of the systemic lupus erythematosus (SLE) classification criteria was to distinguish SLE from other mimic diseases, and to facilitate sample selection in scientific research, they have become widely used as diagnostic criteria in clinical situations. It is not known yet if regarding classification criteria as diagnostic criteria, what problems might be encountered? This is the first study comparing the three sets of classification criteria for SLE, the 1997 American College of Rheumatology (ACR'97), 2012 Systemic Lupus International Collaborating Clinics (SLICC'12) and 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR'19), for their ability to distinguish patients with SLE from patients with pure mucocutaneous manifestations (isolated cutaneous lupus erythematosus without internal disease, i-CLE) in the lupus disease spectrum. 1,865 patients with SLE and 232 patients with i-CLE were recruited from a multicenter study. We found that, due to low specificity, none of the three criteria are adept at distinguishing patients with SLE from patients with i-CLE. SLICC'12 performed best among the original three criteria, but if a positive ANA was removed as an entry criterion, EULAR/ACR'19 would performed better. A review of previous studies that compared the three sets of criteria was presented in this work.

The aryl hydrocarbon receptor: An environmental effector in the pathogenesis of fibrosis.

The aryl hydrocarbon receptor (AhR) is a highly conserved transcription factor that can be activated by small molecules provided by dietary, plant, or microbial metabolites, and environmental pollutants. AhR is expressed in many cell types and engages in crosstalk with other signaling pathways, and therefore provides a molecular pathway that integrates environmental cues and metabolic processes. Fibrosis, which is defined as an aberrant extracellular matrix formation, is a reparative process in the terminal stage of chronic diseases. Both environmental and internal factors have been shown to participate in the pathogenesis of fibrosis; however, the underlying mechanisms still remain elusive. In this review, the potential role of AhR in the process of fibrosis, as well as potential opportunities and challenges in the development of AhR targeting therapeutics, are summarized.

Aryl hydrocarbon receptor signaling activation in systemic sclerosis attenuates collagen production and is a potential antifibrotic target.

Systemic sclerosis (SSc) is a systemic autoimmune disease that often leads to fibrosis of multiple organs, and there are no effective treatments. Aryl hydrocarbon receptor (AhR) is a highly evolutionarily conserved transcription factor activated by endogenous and exogenous ligands and that regulate cell proliferation, tumorigenesis and immune balance. Recently, it have reported AhR signaling may participate in fibrosis process, usually consider as a negative regulator of TGF-ß. However, the detailed relationship between AhR and SSc has not been reported yet. Here we firstly found that AhR and CYP1A1 downregulated in SSc fibroblast(n = 6). The AhR ligand-Ficz negatively regulates TGF-ß1, COL1A1 and α-SMA expression, also enhances the MMP-1 expression via the AhR signaling activation. Conversely the AhR antagonist CH223191 could inhibit this effect. Furthermore, the antifibrosis effect of AhR signaling activation was also confirmed in bleomycin induced scleroderma mouse model. In conclusion, AhR signaling activation balances the extracellular matrix (ECM) composition and deposition, which may provide a new sight to the pathogenesis of SSc and AhR signaling activation may be a potential therapy for SSc.

Safety and efficacy of Rituximab in systemic sclerosis: A systematic review and meta-analysis.

PURPOSE: Rituximab is widely prescribed to treat systemic sclerosis (SSc) by the depletion of pathogenic B cells. Nonetheless, the clinical benefit of Rituximab in SSc remains contentious. This meta-analysis was conducted to systematically evaluate the safety and efficacy profile of Rituximab in SSc patients. PATIENTS AND METHODS: We performed a systematic online query in PubMed, Cochrane, and Web of Science. The available studies on the use of Rituximab in SSc patients were comprehensively reviewed and investigated. RESULTS: In total, 14 studies, including 597 participants, were analyzed. Pooled results showed the long-term improvement in the modified Rodnan skin score (mRSS) for skin function (ΔmRSS: 7.00 at 6 months, 9.70 at 12 months, and 10.93 at 24 months), while forced vital capacity (FVC) (ΔFVC: -0.69 at 6 months, -2.62 at 12 months, and -0.67 at 24 months) and diffusing capacity of the lungs for carbon monoxide (DLCO) (ΔDLCO: -2.39 at 6 months, -3.28 at 12 months, and -0.79 at 24 months) for lung function remained stable in SSc patients after Rituximab treatment. The rate of Rituximab-related adverse events was 12% in the pooled results. CONCLUSION: The pooled results of this meta-analysis indicated that Rituximab is well tolerated, and it is able to improve cutaneous function and stabilize pulmonary function in SSc patients.

Transcriptome Analysis and Emerging Driver Identification of CD8+ T Cells in Patients with Vitiligo.

Activated CD8+ T cells play important roles in the pathogenesis of vitiligo. However, driving factors about the activation and migration of CD8+ T cells remain obscure. In this study, we aim to identify differentially expressed genes (DEGs) and uncover potential factors that drive the disease in melanocyte-specific CD8+ T cells in vitiligo. A total of 1147 DEGs were found through transcriptome sequencing in CD8+ T cells from lesional skin of vitiligo patients and normal controls. Based on KEGG pathway enrichment analysis and PPI, 16 upregulated and 23 downregulated genes were identified. Ultimately, 3 genes were figured out after RT-qPCR verification. The mRNA and protein expression levels of PIK3CB, HIF-1α, and F2RL1 were all elevated in CD8+ T cells from peripheral blood in vitiligo. HIF-1α and PIK3CB were significantly increased in lesional skin of vitiligo. Two CpG sites of the HIF-1α promoter were hypomethylated in vitiligo CD8+ T cells. In conclusion, HIF-1α, F2RL1, and PIK3CB may act as novel drivers for vitiligo, which are all closely associated with reactive oxygen species and possibly contribute to the activation and/or migration of melanocyte-specific CD8+ T cells in vitiligo. In addition, we uncovered a potential role for DNA hypomethylation of HIF-1α in CD8+ T cells of vitiligo.

All-Trans Retinoic Acid Induces CD4+CD25+FOXP3+ Regulatory T Cells by Increasing FOXP3 Demethylation in Systemic Sclerosis CD4+ T Cells.

BACKGROUND: Retinoic acid (RA) is an active metabolite of vitamin A and has been reported to improve the clinical symptoms of patients with systemic sclerosis (SSc). However, the mechanism of RA in the prevention of SSc remains unclear. Regulatory T cells (Tregs) are a subpopulation of T cells with immunosuppressive activity. The quantitative and functional defects of Tregs may mediate the immune dysfunction in SSc. The addition of all-trans retinoic acid (ATRA) to human naïve CD4+ cells could promote the maturation of Tregs and increase the stable expression of Foxp3. In this study, we explored the role of RA on Tregs in SSc CD4+ T cells and its possible epigenetic mechanisms, so as to further understand the mechanisms of RA on SSc. METHODS: CD4+ T cells were isolated from peripheral blood of SSc and treated with or without ATRA and/or transforming growth factor-ß (TGF-ß). The percentage of CD4+CD25+FOXP3+ Tregs was counted by flow cytometry. FOXP3 mRNA and protein levels were measured by quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. Bisulfite sequencing was performed to determine the methylation status of the FOXP3 proximal promoter sequences. RESULTS: The expression of Tregs and FOXP3 in CD4+ T cells from patients with SSc increased in response to ATRA. Moreover, combined stimulation with ATRA and TGF-ß resulted in the enhancement of these effects. Further studies revealed that stimulation with ATRA increased the expression of FOXP3 in SSc CD4+ T cells by downregulating FOXP3 promoter methylation levels. CONCLUSIONS: ATRA acts as an inducer of Treg response in SSc CD4+ T cells via demethylation of the FOXP3 promoter and activation of FOXP3 expression. This may be one of the molecular mechanisms for ATRA, and therefore, RA can be used for the treatment of SSc.