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Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung. To better understand SSc pathogenesis and develop new disease-modifying therapies, it is quite important to understand the complex pathogenesis of SSc from the two distinct perspectives, namely the common pathologic cascade and additional organ-specific pathologies.

Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc. Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.

Therapeutic options for treating advanced melanoma have progressed rapidly in recent decades. Until 6 years ago, the regimen for treating advanced melanoma consisted mainly of cytotoxic agents such as dacarbazine and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have been recognized as anchor drugs for treating advanced melanoma, with or without additional combination drugs such as ipilimumab, but the efficacies of these immunotherapies are not fully satisfactory. In this review, we describe the development of the currently available anti-PD1 Abs-based immunotherapies for advanced melanoma, focusing on their efficacy and immune-related adverse events (AEs), as well as clinical trials still ongoing for the future treatment of advanced melanoma.

Psoriasis is a chronic inflammatory skin disease with a high prevalence of cardiovascular disease (CVD), obesity, dyslipidemia, hypertension, diabetes mellitus, and metabolic syndrome. Among them, CVD is the most common cause of morbidity and mortality in psoriasis patients. Since CVD is associated with considerable morbidity and mortality, primary care clinicians are increasingly committed to reducing the risk of CVD in patients with psoriasis. Biologics targeting TNF-α, IL-12/23, and IL-17 are systemic therapies that can dramatically improve the condition of psoriasis. Recent studies have reported that these inflammatory cytokine signals may promote atherosclerosis, suggesting that biologics might be effective for improving psoriasis as well as reducing the risk of CVD. Here, we reviewed cardiovascular risk in psoriasis patients, the association between psoriatic inflammation and atherosclerosis, and the efficacy of biologics for reducing the risk of cardiovascular diseases.

Dear Editor, Pilomatricoma is a benign tumor characterized by differentiation from hair matrix cells to hair cortical cells. It commonly occurs on the head and neck in young individuals. Although blistering is rare, when present, it is typically observed on the upper arms, shoulders, and back. The condition is more frequently seen in teenagers and young adults; however, it is rare in young children. [...]

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, has emerged as a critical stromal factor that contributes to tumor progression in various malignancies, including skin cancers. Beyond its classical role in inhibiting plasminogen activators, PAI-1 exerts pleiotropic effects within the tumor microenvironment, promoting immunosuppression, angiogenesis, and extracellular matrix remodeling. This review highlights the tumor-promoting functions of PAI-1 in melanoma, cutaneous squamous cell carcinoma, cutaneous angiosarcoma and cutaneous T-cell lymphoma, with a particular focus on its modulation of tumor-associated macrophages, cancer-associated fibroblasts, and endothelial cells. We also discuss recent preclinical and clinical studies targeting PAI-1, including TM5614, a novel oral PAI-1 inhibitor currently under investigation in phase II /III trials. By summarizing the multifaceted roles of PAI-1 and its impact on the immune and stromal landscape of skin malignancies, this review provides a rationale for PAI-1 as a promising therapeutic target and calls for further clinical validation of PAI-1–directed therapies.

Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.

It has been more than a decade since anti-PD-1 and anti-CTLA-4 antibodies were first introduced for the treatment of unresectable melanoma. The advent of these immunotherapies has dramatically transformed the treatment landscape. In recent years, anti-PD-1 antibodies have become the cornerstone of melanoma therapy, and the development of new treatment regimens has advanced rapidly in both Eastern and Western countries. However, clinical practice has revealed lower response rates in East Asian melanoma patients compared to Caucasian populations. This discrepancy may be partially attributed to T cell immune exhaustion within the tumor microenvironment, although the detailed mechanisms remain unclear. Moreover, there is currently no established treatment for BRAF wild-type melanoma that is resistant to anti-PD-1 antibodies. This review discusses the currently available therapeutic strategies for advanced melanoma and addresses the aforementioned challenges, highlighting recent efforts in both Eastern and Western regions.

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents.

Fli1, a member of the Ets transcription factor family, is a key repressor of the human α2(I) collagen (COL1A2) gene. Although our previous studies have delineated that TGF-β induces displacement of Fli1 from the COL1A2 promoter through sequential post-translational modifications, the detailed mechanism by which Fli1 functions as a potent transcriptional repressor of the COL1A2 gene has not been fully investigated. To address this issue, we carried out a series of experiments especially focusing on protein-protein interaction and epigenetic transcriptional regulation. The combination of tandem affinity purification and mass spectrometry identified HDAC1 as a Fli1 interacting protein. Under quiescent conditions, HDAC1 induced deacetylation of Fli1 resulting in an increase of Fli1 DNA binding ability and p300 enhanced this process by promoting the formation of a Fli1-HDAC1-p300 complex. TGF-β-induced phosphorylation of Fli1 at threonine 312 led to disassembly of this protein complex. In quiescent dermal fibroblasts Fli1, HDAC1, and p300 occupied the -404 to -237 region, including the Fli1 binding site, of the COL1A2 promoter. TGF-β induced Fli1 and HDAC1 dissociation from the COL1A2 promoter, while promoting Ets1 and p300 recruitment. Furthermore, acetylation levels of histone H3 around the Fli1 binding site in the COL1A2 promoter inversely correlated with the DNA occupancy of Fli1 and HDAC1, while positively correlating with that of Ets1 and p300. In the functional studies, HDAC1 overexpression magnified the inhibitory effect of Fli1 on the COL1A2 promoter. Moreover, pharmacological blockade of HDAC1 by entinostat enhanced collagen production in dermal fibroblasts. Collectively, these results indicate that under quiescent conditions Fli1 recruits HDAC1/p300 to the COL1A2 promoter and suppresses the expression of the COL1A2 gene by chromatin remodeling through histone deacetylation. TGF-β-dependent phosphorylation of Fli1 at threonine 312 is a critical step regulating the remodeling of the Fli1 transcription repressor complex, leading to transcriptional activation of the COL1A2 gene.