Biology subjects

Petersen, F.

Publications and source records attributed to Petersen, F..

7 recordsLinked to original sources

bioRxiv2026

γδ T cell-derived IL-17A aggravates experimental epidermolysis bullosa acquisita in response to IL-1β

Epidermolysis bullosa acquisita (EBA) is a mucocutaneous autoimmune blistering disorder mediated by autoantibodies against type VII collagen and subsequent splitting of the dermal-epidermal junction. Interleukin (IL)-17A promotes the production of chemokines and cytokines involved in neutrophil recruitment and activation, suggesting that IL-17A may contribute to EBA pathogenesis. We aimed to clarify the role of IL-17A in experimental EBA. Using an antibody transfer-induced EBA mouse model, we demonstrate that IL-17A promotes disease development, as pharmacological blockade of IL-17A with a neutralizing antibody ameliorated skin lesions. Gamma-delta ({gamma}{delta}) T cells were identified as the predominant cellular source of IL-17A, supported by the attenuated disease phenotype observed in {gamma}{delta}TCR-deficient mice. In addition, CD4+ T cells and neutrophils contributed to IL-17A production in experimental EBA. Mechanistically, IL-1-beta, rather than IL-23, was identified as a critical mediator of IL-17A production by {gamma}{delta} T cells in vitro, consistent with our in vivo findings. Whereas EBA severity was not reduced in IL-23p19-deficient mice, disease was markedly attenuated in IL-1R-deficient animals. Together, our study provides the first evidence that {gamma}{delta} T cell-derived IL-17A plays a pivotal role in experimental EBA and identifies a previously unrecognized IL-1{beta}/{gamma}{delta} T cell/IL-17A axis that expands current understanding of EBA immunopathogenesis.

immunology↗

bioRxiv2026

Targeting neutrophil signaling networks in immune complex-mediated autoimmune disease

Fragment crystallizable gamma receptor (Fc{gamma}R)-induced signaling is a crucial process that determines the cellular response to immune complexes (IC) in autoimmune diseases. In several diseases including pemphigoid diseases (PD), such as epidermolysis bullosa acquisita (EBA), or rheumatoid arthritis (RA), neutrophils are prominently involved as effector cells, while others such as immune thrombocytopenia (ITP) are independent of neutrophils. At the same time, most diseases are commonly treated by broad-range immunosuppression accompanied by severe risk for adverse effects. Signal transduction inhibitors (STIs) have been successfully applied in cancer therapy. However, their use in autoimmune diseases is an emerging, but so far understudied potential treatment avenue. Therefore, we screened a target-selective compound library consisting of 155 STIs in a neutrophil-based assay and conducted a multiplex kinase activity profiling with IC-stimulated neutrophils. Thus, we found novel potential therapeutic targets that were validated both in vitro in functional neutrophil assays and in vivo in murine models of EBA Here, we demonstrate that both systemic and topical treatment with several individual STIs is effective in a prophylactic approach in these models. Furthermore, therapeutic treatment with the BTK inhibitor ibrutinib in the immunization-induced EBA model reduced disease severity by approximately 85 % and showed efficacy in additional experimental models of EBA, arthritis, and ITP. Together, the present study contributes to the elucidation of Fc{gamma}R-dependent signaling in neutrophils and identifies multiple novel promising treatment options including inhibition of PLC, PDK-1, PKC, p38, DNA-PK, KSP, c-Met, TBK-1 and BTK for IC-mediated autoimmune diseases.

immunology↗

bioRxiv2025

CDK7, CDK9, or CDK11 Inhibition Reduces Neutrophil-Driven Inflammation and Tissue Damage in Experimental Autoimmune Models

BackgroundCyclin-dependent kinases (CDKs) are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap formation, or apoptosis. Since these mechanisms are implicated in multiple autoimmune diseases, we aimed to delineate the role of CDKs in IC-mediated autoimmune diseases both in vitro and in vivo. MethodsWe analyzed CDK gene expression in unstimulated and immune complex (IC)-stimulated neutrophils. Subsequently, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. To analyze the inhibitors in a more translational approach, we proceeded with the systemic and topical application of the effective inhibitors in a murine antibody transfer-induced local epidermolysis bullosa acquisita (EBA) model. The most efficient inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: Serum-transfer arthritis (STA), which also, but not exclusively, depends on neutrophils and immune thrombocytopenia (ITP), which is considered less neutrophil-dependent. ResultsWe found 14 CDKs expressed in unstimulated cells, while the IC-stimulation showed an upregulation of CDK2 and CDK4 expression. Inhibitors selectively targeting CDK1, CDK2, CDK4/6, CDK7, CDK9, CDK11, and CDK12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro. In the predominantly neutrophil-driven EBA model, we observed a reduction of disease severity upon treatment with CDK7, CDK9, or CDK11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964, respectively, also improved the clinical phenotype. In line with our hypothesis, MC180295 impaired the development of STA, but not ITP. ConclusionsCDK7, CDK11, and especially CDK9 inhibition show therapeutic potential in IC-driven neutrophil-mediated diseases such as rheumatoid arthritis and EBA.

immunology↗

bioRxiv2025

ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita

Neutrophils are key effector cells in antibody-mediated autoimmune diseases, contributing to inflammation via the release of reactive oxygen species (ROS). Extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is expressed in neutrophils but its role in autoimmune disease pathogenesis remains unclear. We investigated the functional relevance of ERK5 in antibody-mediated autoimmune diseases by comparing neutrophil-dependent (epidermolysis bullosa acquisita, EBA; serum transfer arthritis, STA) and neutrophil-independent (immune thrombocytopenia, ITP) murine models using the small-molecule ERK5 inhibitor XMD8-92. In vitro, pharmacological ERK5 inhibition specifically reduced neutrophil ROS release and CD62L shedding without affecting adhesion, chemotaxis, or CD18 expression. No major effects on viability were observed. In vivo, ERK5 inhibition with XMD8-92 significantly ameliorated antibody transfer-induced EBA, supporting a critical role of neutrophil-derived ROS in disease pathogenesis. In STA and ITP, ERK5 inhibition did not affect clinical outcomes. Together, these findings highlight ERK5 as a regulator of neutrophil ROS release and a potential therapeutic target in ROS-driven autoimmune diseases such as EBA.

immunology↗

bioRxiv2023

Genome assembly of the bearded iris Iris pallida Lam.

Irises are perennial plants, representing a large genus with hundreds of species. While cultivated extensively for their ornamental value, commercial interest in irises lies in the secondary metabolites present in their rhizomes. The Dalmatian Iris (Iris pallida Lam.) is an ornamental plant that also produces secondary metabolites with potential value to the fragrance and pharmaceutical industries. In addition to providing base notes for the fragrance industry, iris tissues and extracts possess anti-oxidant, anti- inflammatory, and immunomodulatory effects. However, study of these secondary metabolites has been hampered by a lack of genomic information, instead requiring difficult extraction and analysis techniques. Here, we report the genome sequence of Iris pallida Lam., generated with Pacific Bioscience long-read sequencing, resulting in a 10.04 Gbp assembly with a scaffold N50 of 14.34 Mbp and 91.8% complete BUSCOs. This reference genome will allow researchers to study the biosynthesis of these secondary metabolites in much greater detail, opening new avenues of investigation for drug discovery and fragrance formulations. Research area: Genetics and Genomics; Botany; Plant Genetics

plant biology↗

bioRxiv2020

Expression of ACE2, TMPRSS2, and CTSL in human airway epithelial cells under physiological and pathological conditions: Implications for SARS-CoV2 infection

SARS-CoV-2 enters into human airway epithelial cells via membrane fusion or endocytosis, and this process is dependent on ACE2, TMPRSS2, and cathepsin L. In this study, we examined the expression profiles of the three SARS-CoV-2 entry-related genes in primary human airway epithelial cells isolated from donors with different physiological and pathological backgrounds such as smoking, COPD, asthma, lung cancer, allergic rhinitis, cystic fibrosis, or viral infections. By reanalyzing 54 GEO datasets comprising transcriptomic data of 3428 samples, this study revealed that i) smoking is associated with an increased expression of ACE2 and TMPRSS2 and a decreased expression of cathepsin L; ii) infection of rhinovirus as well as poly(I:C) stimulation leads to high expression of all three SARS-CoV-2 entry-related genes; iii) expression of ACE2 and cathepsin L in nasal epithelial cells are decreased in patients with asthma and allergic rhinitis. In conclusion, this study implicates that infection of respiratory viruses, cigarette smoking and allergic respiratory diseases might affect the susceptibility to and the development of COVID-19.

pathology↗

bioRxiv2019

Investigating the biochemical properties of Streptococcal polysaccharide capsules using atomic force microscopy

In common with many bacterial pathogens, Streptococcus pneumoniae has a polysaccharide capsule, which facilitates immune evasion and is a key virulence determinant. However, recent data has shown that the closely related Streptococcus mitis can also express polysaccharide capsules including those with an identical chemical structure to S. pneumoniae capsular serotypes. We have used atomic force microscopy (AFM) techniques to investigate the biophysical properties of S. mitis and S. pneumoniae strains expressing the same capsular serotypes that might relate to their differences in virulence potential. When comparing S. mitis and S. pneumoniae strains with identical capsule serotypes S. mitis strains were more susceptible to neutrophil killing and imaging using electron microscopy and AFM demonstrated significant morphological differences. Force-volume mapping using AFM showed distinct force-curve profiles for the centre and edge areas of encapsulated S. pneumoniae and S. mitis strains. This \"edge effect\" was not observed in the unencapsulated streptococcal strains and in an unencapsulated Staphylococcus aureus strain, and therefore was a direct representation of the mechanical properties of the bacterial capsule. When two strains of S. mitis and S. pneumoniae expressed an identical capsular serotype, they presented also similar biomechanical characteristics. This would infer a potential relationship between capsule biochemistry and nanomechanics, independent of the bacterial strains. Overall, AFM was an effective tool to explore the biophysical properties of bacterial capsules of living bacteria by reproducibly quantifying the elastic and adhesive properties of bacterial cell surfaces. Using AFM to investigate capsule differences over a wider range of strains and capsular serotypes of streptococci and correlate the data with phenotypic differences will elucidate how the biophysical properties of the capsule can influence its biological role during infection.

microbiology↗