Biology subjects

Stary, G.

Publications and source records attributed to Stary, G..

6 recordsLinked to original sources

bioRxiv2026

Alternatively polarized neutrophils metabolically restrain macrophage-driven inflammation

Macrophage-driven inflammation underlies many inflammatory diseases, yet the mechanisms that restrain macrophage activation within inflamed tissues remain poorly understood. Using mouse models of foreign body granuloma formation and macrophage activation syndrome, we show that neutrophils accumulate at sites of inflammation and metabolically restrain macrophage-driven pathology. Neutrophil depletion or genetic impairment exacerbated tissue pathology, whereas induced neutrophilia attenuated inflammatory damage. Tissue-infiltrating neutrophils acquired an alternatively polarized state characterized by high arginase 1 activity that was regulated by an IL4Ra-STAT3-NOX2 signaling axis. Functionally, polarized neutrophils depleted extracellular arginine in an arginase 1-dependent manner, thereby limiting macrophage effector programs. Human neutrophils exhibited conserved regulation of arginase activity, and alternatively polarized neutrophils were detected in patients with sarcoidosis and macrophage activation syndrome. Together, these findings identify an arginine-dependent metabolic mechanism through which alternatively polarized neutrophils restrain macrophage-driven inflammation and reveal a previously unrecognized immune-regulatory role for these cells in chronic inflammatory disease.

immunology↗

bioRxiv2026

Prevalent glutamyl-endopeptidases in the commensal skin microbiome have itch-relevant activity

Atopic dermatitis (AD) is frequently accompanied by pruritus, which has predominantly been attributed to skin colonization by Staphylococcus aureus, particularly through cleavage of protease-activated receptor 1 (PAR1) by the glutamyl endopeptidase (GEP) V8 protease. Whether related GEPs from other skin-associated staphylococci contribute to this process remains unclear. Here, we analyzed 273 staphylococcal isolates from skin swabs of 10 AD patients with pruritus, dominated by S. aureus and Staphylococcus epidermidis. Genome mining using a custom hidden Markov model identified 678 candidate GEPs, which were clustered and resolved into five structurally distinct protease architectures. Representative proteases (V8, Esp, SplB, Csp, and Hsp) were expressed and characterized. Esp displayed GEP activity and PAR1 tethered-ligand cleavage comparable to V8, generating noncanonical cleavage products, while Csp cleaved PAR1 with reduced but substantial efficiency. All representative proteases significantly disrupted barrier integrity in an epithelial barrier model. Analysis of isolate genomes and publicly available Staphylococcus genomes showed that V8 and Esp are highly conserved and largely species-restricted, whereas Csp is more broadly distributed across species. These findings identify Esp and Csp as functional GEP virulence factors in S. epidermidis and S. capitis, capable of activating itch signaling and compromising barrier function. Our study suggests that GEP-mediated pruritus and barrier dysfunction in AD may arise not only from pathogens like S. aureus, but also from commensals or opportunistic pathogens such as S. epidermidis and S. capitis. ImportanceStaphylococcus aureus colonization on the skin is closely associated with itch in atopic dermatitis (AD) through a secreted protease that cleaves PAR1 on sensory neurons. However, AD patients can experience pruritus without S. aureus colonization. This raises the question of whether other skin-colonizing staphylococci contribute to this process. We identify glutamyl endopeptidase homologs, including Esp from Staphylococcus epidermidis and Csp from Staphylococcus capitis, that cleave the same itch receptor and disrupt epithelial barrier integrity. These serine proteases are distributed across staphylococcal species that colonize human skin. Therefore, itch and barrier dysfunction in AD may not be restricted to S. aureus but instead arise from the proteolytic activity of multiple staphylococcal species. This functional redundancy means that other staphylococcal species can sustain GEP-driven itch and barrier dysfunction even in the absence of S. aureus, suggesting that therapeutic strategies targeting only S. aureus may overlook these alternative drivers of disease.

microbiology↗

bioRxiv2025

Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis

Endothelial cells (ECs) are critical regulators of vascular function and exhibit specialized, organ-specific roles across tissues. During aging, these cells become dysfunctional, resulting in increased susceptibility to cardiovascular disease and its associated mortality. While single-cell transcriptomics studies have revealed extensive endothelial heterogeneity across tissues and conditions, a comprehensive atlas of human EC transcriptomes over the course of the adult human lifespan is still lacking. Here, we present the Human Aging Endothelial Cell Atlas (HAECA), a harmonized single-cell transcriptomic compendium of over 375,000 ECs from 12 human tissues throughout adulthood. Using HAECA, we identified age-associated transcriptional shifts, including a decline in angiogenic gene expression in venous ECs and widespread alterations in extracellular matrix (ECM)- and mechanotransduction-associated pathways. We validated these findings in aging human skin and further uncovered a p21-linked transcriptional program in ECs, confirmed in both in vitro and in vivo models and linked to cellular senescence. Together, our study provides a high-resolution transcriptome reference across spatial as well as temporal axes of the human endothelium.

cell biology↗

bioRxiv2024

Spermidine/spermine N1-acetyltransferase controls tissue-specific regulatory T cell function in chronic inflammation

Regulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, Tregs fail to control effector T cell responses. The causes of Treg dysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Treg function. Here we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to uncover SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Treg dysfunction during TH17-mediated inflammation. Tregs expressing SAT1 exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived Tregs increased expression of SAT1 leads to a loss of suppressive function and a switch to a TH17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a TH17 microenvironment. Finally, the potential therapeutic impact of targeting SSAT was demonstrated in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued Treg number and function in the skin and systemically. Together, these data show that SAT1 expression has severe functional consequences on Tregs and provides a novel target to treat chronic inflammatory skin disease.

immunology↗

bioRxiv2023

Scarring hair follicle destruction is driven by the collapse of EGFR-protected JAK-STAT1-sensitive stem cell immune privilege

The hair follicle stem cell niche is an immune-privileged microenvironment, characterised by suppressed antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrate the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) from scarring hair follicle degeneration. Mechanistically, disruption of EGFR signalling generates a cell intrinsic hypersensitivity within the JAK-STAT1 pathway, compromising the immune privilege in the context of CD8 T cell and NK cell-mediated inflammation. Genetic depletion of either JAK1/2 or STAT1 or topical therapeutic inhibition of JAK1/2 restores the immune privilege and activates stem cells to resume hair growth in mouse models of epidermal and hair follicle specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and from EGFR-independent cicatricial alopecia patients indicate active STAT1 signalling within the hair follicles. Notably, a case study of folliculitis decalvans, characterised by progressive hair loss, scaling and perifollicular erythema, demonstrates successful treatment with systemic JAK1/2 inhibition. Our findings offer mechanistic insights and present a therapeutic strategy for addressing scarring hair follicle destruction associated with EGFR-inhibitor therapy and cicatricial alopecia.

immunology↗

bioRxiv2023

Mast cell-derived BH4 is a critical mediator of postoperative pain

Postoperative pain affects most patients after major surgery and can transition to chronic pain. Here, we discovered that postoperative pain hypersensitivity correlated with markedly increased local levels of the metabolite BH4. Gene transcription and reporter mouse analyses after skin injury identified neutrophils, macrophages and mast cells as primary postoperative sources of GTP cyclohydrolase-1 (Gch1) expression, the rate-limiting enzyme in BH4 production. While specific Gch1 deficiency in neutrophils or macrophages had no effect, mice deficient in mast cells or mast cell-specific Gch1 showed drastically decreased postoperative pain after surgery. Skin injury induced the nociceptive neuropeptide substance P, which directly triggers the release of BH4-dependent serotonin in mouse and human mast cells. Substance P receptor blockade substantially ameliorated postoperative pain. Our findings underline the unique position of mast cells at the neuro-immune interface and highlight substance P-driven mast cell BH4 production as promising therapeutic targets for the treatment of postoperative pain.

immunology↗