Biology subjects

Ernst, N.

Publications and source records attributed to Ernst, N..

5 recordsLinked to original sources

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

Murine CMV Infection Unmasks Macrophage-Driven Inflammatory Cardiomyopathy in Pkp2, but not in Ttn Mutant Mice

2.BackgroundGenetic cardiomyopathies display variable penetrance and phenotypic expression, highlighting the influence of environmental modulators. Myocarditis, commonly triggered by cardiotropic viruses, overlaps clinically with genetic cardiomyopathies. Consequently, these infections are implicated as secondary factors that accelerate disease onset and progression, yet their precise impact in specific genetic settings remains unexplored. MethodsTo interrogate this, genetic mouse models heterozygous for a mutant allele of desmosomal plakophilin-2 (Pkp2+/-) or sarcomeric titin (Ttn+/-), genes frequently linked to acute myocarditis, were challenged with murine cytomegalovirus (MCMV) to determine how latent infection influences myocardial inflammation, tissue remodeling, and cardiac performance. Integrated experimental approaches, including echocardiography, histology, flow cytometry, single-cell RNA sequencing, as well as cytokine and kinome analyses, defined immune and signaling responses in infected versus non-infected hearts. ResultsAcute, MCMV-induced viral myocarditis and subsequent latent MCMV infection unmasked early disease onset in Pkp2+/- animals, leading to progressive systolic impairment, whereas in Ttn+/- mice cardiac structure and function remained preserved throughout infection. Cardiac immune profiling uncovered infection- and genotype-specific divergence: both genetic models showed a stable myocardial effector-memory CD8+ T-cell response to MCMV, but only Pkp2+/- hearts recruited additional Ly6C+ CCR2+ monocytes and macrophages with distinct inflammatory signatures. In the absence of infection, Pkp2 insufficiency initiated subclinical CCL2 secretion and subsequent recruitment of CCR2+ cells, reflecting early immune activation preceding age-associated functional and structural decline. At this stage, cytokine and kinase evaluations indicated a balance between proinflammatory and compensatory signals. However, with aging or following MCMV challenge, this balance shifted towards persistent inflammation, evidenced by chronic upregulation of cytokines and activation of signaling pathways, which ultimately led to adverse effects and myocardial dysfunction. ConclusionsManifestation of genetic cardiomyopathies depends on interactions between inherited susceptibility and environmental stressors. Here, we show that cytomegalovirus infection intensifies inflammation in PKP2-related cardiomyopathy. In contrast, TTN-linked cardiomyopathy does not exhibit increased inflammation under the same conditions. For individuals carrying desmosomal variants, infection control and tailored anti-inflammatory strategies may attenuate or delay disease manifestation and progression.

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↗

bioRxiv2024

Aerobic capacity and exercise mediate protection against hepatic steatosis via enhanced bile acid metabolism.

High cardiorespiratory fitness and exercise show evidence of altering bile acid (BA) metabolism and are known to protect or treat diet-induced hepatic steatosis, respectively. Here, we tested the hypothesis that high intrinsic aerobic capacity and exercise both increase hepatic BA synthesis measured by the incorporation of 2H2O. We also leveraged mice with inducible liver-specific deletion of Cyp7a1 (LCyp7a1KO), which encodes the rate-limiting enzyme for BA synthesis, to test if exercise-induced BA synthesis is critical for exercise to reduce hepatic steatosis. The synthesis of hepatic BA, cholesterol, and de novo lipogenesis was measured in rats bred for either high (HCR) vs. low (LCR) aerobic capacity consuming acute and chronic high-fat diets. HCR rats had increased synthesis of cholesterol and certain BA species in the liver compared to LCR rats. We also found that chronic exercise with voluntary wheel running (VWR) (4 weeks) increased newly synthesized BAs of specific species in male C57BL/6J mice compared to sedentary mice. Loss of Cyp7a1 resulted in fewer new BAs and increased liver triglycerides compared to controls after a 10-week high-fat diet. Additionally, exercise via VWR for 4 weeks effectively reduced hepatic triglycerides in the high-fat diet-fed control male and female mice as expected; however, exercise in LCyp7a1KO mice did not lower liver triglycerides in either sex. These results show that aerobic capacity and exercise increase hepatic BA metabolism, which may be critical for combatting hepatic steatosis. HighlightsO_LIRats with intrinsic high aerobic capacity have more significant reductions in de novo lipogenesis and increased cholesterol and bile acid synthesis on a high-fat diet compared to rats with low aerobic capacity. C_LIO_LIChronic exercise increases hepatic bile acid synthesis in mice. C_LIO_LILoss of Cyp7a1 blunts the capacity for exercise to increase bile acid synthesis and treat hepatic steatosis in male and female mice fed a high-fat diet. C_LI

physiology↗