Biology subjects

Korosec, A.

Publications and source records attributed to Korosec, A..

3 recordsLinked to original sources

bioRxiv2025

Nicotinamide N-Methyltransferase drives fibroblast activation and skin fibrosis in systemic sclerosis

BackgroundIn systemic sclerosis (SSc), an autoimmune response leads to progressive fibrosis of the skin and internal organs, driven by aberrant activation of fibroblasts. The mechanisms dictating persistent dermal fibroblast (DF) activation and production of extracellular matrix (ECM) remain poorly understood. Nicotinamide N-methyltransferase (NNMT), a SAM-consuming enzyme that modulates cellular methylation potential, has been implicated in fibrotic tissue remodelling in metabolic and malignant diseases. Here, we identify NNMT as a key determinant in DF activation and fibrosis in SSc. MethodsWe analyzed bulk, single-cell RNA-Seq and spatial transcriptomics datasets from SSc skin. Functional studies were performed in TGF{beta}-activated primary human DFs using siRNA-mediated NNMT knockdown (KD) combined with RNA-Seq, metabolite profiling, ELISA, and western blotting. The role of NNMT-regulated transcription factors was assessed by QuantSeq 3' RNA-Seq following ATF4, SOX9, or SRF KD. FindingsNNMT was markedly upregulated in SSc skin and enriched in disease-expanded SFRP2/COL8A1 myofibroblast states. NNMT KD restored methylation balance by increasing the SAM/SAH ratio and H3K27me3 levels, and abrogated TGF{beta}-induced profibrotic programs regulating ECM production and collagen synthesis. Mechanistically, NNMT was required for TGF{beta}-induced upregulation of the transcription factors ATF4, SOX9, and SRF, which together orchestrate ECM gene expression and COL1A1 secretion. InterpretationThese findings define a previously unrecognized TGF{beta}-NNMT-ATF4/SOX9/SRF axis that coordinates profibrotic transcriptional programs in DFs. Accordingly, NNMT functions as a central effector linking TGF{beta} signaling to DF activation and ECM remodelling. Targeting NNMT may thus represent a promising therapeutic strategy to attenuate skin fibrosis in SSc.

immunology↗

bioRxiv2023

CAF variants control the tumor-immune microenvironment and predict skin cancer malignancy

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the yet unresolved intra-tumoral variety of CAFs in three skin cancer types -- Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma -- at molecular and spatial single-cell resolution. By integral analysis of the fibroblasts with the tumor microenvironment, including epithelial, mesenchymal, and immune cells, we characterize three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Notably, large cohort tissue analysis reveals marked shifts in CAF subtype patterns with increasing malignancy. Two CAF types exhibit immunomodulatory capabilities via distinct mechanisms. mCAFs synthesize extracellular matrix and have the ability to ensheath tumor nests, potentially limiting T cell invasion in low-grade tumors. In contrast, iCAFs are enriched in late-stage tumors, especially infiltrative BCC and high-grade melanoma, and express unexpectedly high mRNA and protein levels of cytokines and chemokines, pointing to their integral role in immune cell recruitment and activation. This finding is further supported by our observation that in vitro exposure of primary healthy fibroblasts to skin cancer cell secretomes induces an iCAF-like phenotype with immunomodulatory functions. Thus, targeting CAF variants, particularly the immunomodulatory iCAF subtype, holds promise for improved efficacy of immunotherapy in skin cancers.

cancer biology↗

bioRxiv2022

A neutrophil-B-cell axis governs disease tolerance during sepsis via Cxcr4

Sepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multi-organ failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce. Here, we established a model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that, both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils, included upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted tissue tolerance by suppressing tissue damaging properties of neutrophils. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue tolerance and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis. SummaryWe show that a B cell/neutrophil interaction in the bone marrow facilitates tissue tolerance during severe sepsis. By affecting neutrophil Cxcr4 expression, B cells can impact neutrophil effector functions. Finally, therapeutic activation of Cxcr4 successfully promoted tissue tolerance and prevented liver damage during sepsis.

immunology↗