Dermatology
Abstract
Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a rare inflammatory skin disorder characterized by erythematous plaques with a dense dermal neutrophilic infiltrate. First-line therapy remains oral corticosteroids, which suppresses inflammation non-specifically. Although neutrophils are typically short-lived, how they persist in Sweet syndrome skin and contribute to disease pathogenesis remains unclear. Here, we identify a previously unrecognized population of antigen-presenting cell (APC)-like neutrophils expressing MHC class II genes that are uniquely present in Sweet syndrome skin but absent from healthy tissue and circulation. Keratinocytes extended neutrophil lifespan 10-fold in co-culture experiments and drove the emergence of an APC-like phenotype in approximately 30% of neutrophils, mirroring observations in patient lesions. Mechanistically, keratinocyte-derived serum amyloid A1 (SAA1) signals through the formyl peptide receptor 2 (FPR2) on neutrophils to promote their survival. These long-lived neutrophils actively orchestrate local immune responses by recruiting T cells and inducing cytokine production. Strikingly, dual blockade of SAA1-FPR2 signaling restores neutrophil turnover to baseline levels, with efficacy comparable to high-dose corticosteroids. These findings uncover a keratinocyte-neutrophil-T cell axis that sustains chronic inflammation in Sweet syndrome and highlight the SAA1/FPR2 pathway as a promising target for precision therapy.
Authors
Jianhe Huang, Satish Sati, Olivia Ahart, Emmanuel Rapp-Reyes, Linda Zhou, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
Abstract
Calciphylaxis is a rare but life-threatening disorder characterized by ectopic calcification affecting the subcutaneous tissues and blood vessels of the skin. Once diagnosed, survival rates are less than a year and yet despite the severity of the condition, the pathobiology of calciphylaxis is ill understood. Here, we create animal models of calciphylaxis that recapitulate many characteristics of the human phenotype. We demonstrate that cutaneous calcification is preceded by inflammatory cell infiltration. We show that increased local skin inflammation, regardless of the inciting cause, in the presence of hypercalcemia and hyperphosphatemia contributes to cutaneous ectopic calcification. Genetically modified rodents lacking immune activation of T and B cells or NK cells are resistant to developing cutaneous calcification. Consistent with this, administration of the immunosuppressive cyclophosphamide rescued calcific deposits as did T cell suppression with cyclosporine. We demonstrate IL17 is upregulated in calcific skin and neutrophils are the predominant cell types expressing IL 17 and tissue alkaline phosphatase that is necessary for ectopic calcification. Targeting IL17 with a monoclonal antibody or using a myeloperoxidase inhibitor to blunt neutrophil activation notably attenuated calcific deposits in vivo. Taken together, these observations provide fresh insight into the role of the immune system and the IL17/neutrophil axis in mediating ectopic calcification in rodent models of calciphylaxis.
Authors
Bo Tao, Edward Z. Cao, James Hyun, Sivakumar Ramadoss, Juan F. Alvarez, Lianjiu Su, Qihao Sun, Zhihao Liu, Linlin Zhang, Alejandro Espinoza, Yiqian Gu, Feiyang Ma, Shen Li, Matteo Pellegrini, Arjun Deb
Abstract
Few effective therapeutic options exist following progression on immune checkpoint blockade (ICB) for melanoma. Here we utilize a platform incorporating transcriptomic profiling, high-throughput drug screening (HTDS) and murine models to demonstrate the pre-clinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. HTDS targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and following progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.
Authors
Imran Khan, Aida Rodriguez-Brotons, Anukana Bhattacharjee, Vladimir Bezrookove, Altaf Dar, David De Semir, Mehdi Nosrati, Ryan Ice, Liliana Soroceanu, Stanley P. Leong, Kevin B. Kim, Yihui Shi, James E. Cleaver, James R. Miller, Pierre-Yves Desprez, John M. Kirkwood, Marcus Bosenberg, Nathan Salomonis, Sean McAllister, Mohammed Kashani-Sabet
Abstract
Authors
James G. Krueger, Mrinal K. Sarkar, Mark G. Lebwohl, Akimichi Morita, Kenneth Gordon, Rachael Bogle, Christopher Cole, Anthony Coon, Richard G. Langley, Richard B. Warren, Arash Mostaghimi, Bruce Strober, A. David Burden, Min Zheng, Aaron R. Mangold, Milan J. Anadkat, Jonathan N. Barker, Joseph F. Merola, Lam C. Tsoi, Ming Tang, Kolja Becker, Denis Delic, Christian Thoma, Johann E. Gudjonsson
Abstract
Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that angiopoietin-like protein 2 (ANGPTL2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, ANGPTL2 upregulates pro-fibrotic genes, downregulates various junctional proteins, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, ANGPTL2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.
Authors
Dyuti Saha, Ravi Kiran Annadorai, Sujaya Thannimangalath, Neha P. Shroff, Sunny Kataria, Binita Dam, Abhik Dutta, Akshay Hegde, Ankita Hiwale, Venkatesh Ravula, Shagnik Saha, Lekshmi Minikumari Rahulan, Neha Nigam, Neha Singh, Vikas Agarwal, Praveen K. Vemula, Colin Jamora
Abstract
Psoriatic arthritis (PsA) is a multifaceted chronic inflammatory disease affecting the skin, joints, and entheses, and is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement, however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermal-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2-STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF𝜶 production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1-CXCL10-periarticular CD14hi macrophages-TNFα axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.
Authors
Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man
Abstract
Human cutaneous leishmaniasis (CL) is characterized by chronic skin pathology. Experimental and clinical data suggest that immune checkpoints (ICs) play a crucial role in disease outcome, but the cellular and molecular niches that facilitate IC molecule expression during leishmaniasis are ill defined. In Sri Lankan patients with CL, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death–ligand 1 (PD-L1) were enriched in skin lesions, and reduced PD-L1 expression early after treatment initiation was predictive of a cure rate following antimonial therapy. Here, we used spatial cell interaction mapping to identify IL-32–expressing CD8+ memory T cells and Tregs as key components of the IDO1/PD-L1 niche in Sri Lankan patients with CL and in patients with distinct forms of dermal leishmaniasis in Brazil and India. Furthermore, the abundance of IL-32+ cells and IL-32+CD8+ T cells at treatment initiation was negatively correlated with the rate of cure in Sri Lankan patients. This study provides insights into the spatial mechanisms underpinning IC expression during CL and offers a strategy for identifying additional biomarkers of treatment response.
Authors
Nidhi S. Dey, Shoumit Dey, Naj Brown, Sujai Senarathne, Luiza Campos Reis, Ritika Sengupta, Jose A.L. Lindoso, Sally R. James, Lesley Gilbert, Dave Boucher, Mitali Chatterjee, Hiro Goto, Shalindra Ranasinghe, Paul M. Kaye
Abstract
Background: Tebentafusp is the first T-cell receptor-based bispecific protein approved for clinical use in HLA-A*02:01+ adult patients with unresectable/metastatic uveal melanoma. It redirects T-cells toward gp100-expressing target cells, frequently inducing skin-related early adverse events. Methods: This study investigated immunological and cellular responses using single-cell and spatial analysis of skin biopsies from patients with metastatic uveal melanoma treated with tebentafusp. Results: 81.8% of patients developed acute cutaneous adverse events, which correlated with improved survival. Multimodal analysis revealed a brisk infiltration of CD4+ and CD8+ T-cells, while melanocyte numbers declined. Single-cell RNA-sequencing revealed T-cell activation, proliferation, and IFN-γ/cytotoxic gene upregulation. CD8+ T-cells co-localized with melanocytes and upregulated LAG3, suggesting potential for combination therapies with tebentafusp. Melanocytes upregulated antigen presentation and apoptotic pathways, while pigmentation gene expression decreased. However, gp100 remained stably expressed. Conclusion: Sequential skin biopsies enable in vivo pharmacodynamic modeling of tebentafusp, offering insights into immune activation, toxicity, and treatment response. Examining the on-target effects of bispecifics in tissues amenable to longitudinal sampling enhances our understanding of toxicity and therapeutic escape mechanisms, guiding strategies for treatment optimization.
Authors
Ramon Staeger, Aizhan Tastanova, Adhideb Ghosh, Nicola Winkelbeiner, Prachi Shukla, Isabel Kolm, Patrick Turko, Adel Benlahrech, Jane Harper, Anna Broomfield, Antonio Camera, Marianna Ambrosio, Veronika Haunerdinger, Phil F. Cheng, Egle Ramelyte, James P. Pham, Stefanie Kreutmair, Burkhard Becher, Mitchell P. Levesque, Reinhard Dummer, Barbara Meier-Schiesser
Abstract
Authors
Yue Zhang, Julia A. Yescas, Kristy Tefft, Spencer Ng, Kevin Qiu, Erica B. Wang, Shifa Akhtar, Addie Walker, Macartney Welborn, Martin Zaiac, Joan Guitart, Aamir M. Qureshi, Youn H. Kim, Michael S. Khodadoust, Naiem T. Issa, Jaehyuk Choi
Abstract
Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.
Authors
Jiawen Yang, James T. Lim, Paul Victor Santiago Raj, Marcelo G. Corona, Chen Chen, Hunain Khawaja, Qiong Pan, Gillian D. Paine-Murrieta, Rick G. Schnellmann, Denise J. Roe, Prafulla C. Gokhale, James A. DeCaprio, Megha Padi
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)