Biology subjects

Schabbauer, G.

Publications and source records attributed to Schabbauer, G..

4 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↗

bioRxiv2025

IRF4 is a master regulator of multinucleated giant cell formation

Multinucleated giant cells (MGCs) are a hallmark pathological feature of a wide range of diseases, yet the mechanisms underlying their formation and function remain poorly understood. Although it is recognized that MGCs arise from a heterogeneous pool of myeloid precursors, how a committed MGC fate develops therein remains unknown. Here, combining temporal in vitro and in vivo differentiation of bone marrow-derived myeloid precursors with single cell and bulk RNA sequencing as well as CRISPR/Cas9-mediated gene editing, we shed insight into how MGCs emerge. Our findings reveal that coordinated upregulation of cell fusion genes and cellular metabolism, particularly oxidative phosphorylation, regulate the transition from macrophage progenitors to fusion competent cells. In vivo fate-mapping unveils Ms4a3-, and Cd11c-but not Cx3cr1-traced cells as the predominant precursor populations for MGCs in a lung granuloma formation model. Notably, transcription factor profiling in the progression from early myeloid precursors to pre-MGCs identifies IRF4 as a key molecular switch driving MGC generation. IRF4+ MGCs are present in different pathologies, including Schistosoma mansoni egg induced granulomas, Aspergillus fumigatus conidia mediated allergic airway inflammation and human head and neck squamous cell carcinomas. Mechanistically, IRF4 controls critical fusion related genes such as Dcstamp and Ocstamp. Consequently, Irf4 deficient cells are unable to develop into MGCs. Collectively, our work delineates the trajectory of MGC differentiation, establishing IRF4 as a defining transcription factor required for the generation of fusion-competent progenitors that ultimately give rise to MGCs.

immunology↗

bioRxiv2020

MiR-146a controls age related bone loss

Bone loss is one of the consequences of aging, leading to diseases such as osteoporosis and increased susceptibility to fragility fractures and therefore considerable morbidity and mortality in humans. Here we identify microRNA 146a as an essential epigenetic switch controlling bone loss with age. Mice deficient in miR-146a show regular development of their skeleton. However, while WT mice start to lose bone with age, animals deficient in miR-146a continue to accrue bone throughout their life span. Increased bone mass is due to increased generation and activity of osteoblasts in miR-146a deficient mice as a result of sustained activation of bone anabolic Wnt signaling during aging. Deregulation of the miR-146a target genes Wnt1 and Wnt5a parallel bone accrual and osteoblast generation, which is accompanied by reduced development of bone marrow adiposity. Furthermore, miR-146a deficient mice are protected from ovariectomy induced bone loss. In humans, levels of miR-146a are increased in patients suffering fragility fractures in comparison to those who do not. These data identify miR-146a as a crucial epigenetic temporal regulator which essentially controls bone homeostasis during aging by regulating bone anabolic Wnt signaling. Therefore, miR-146a might be a powerful therapeutic target to prevent age related bone dysfunction such as the development of bone marrow adiposity and osteoporosis.

molecular biology↗

bioRxiv2019

Ifnar1 signaling breaks the hepatic urea cycle to regulate adaptive immunity

Infections induce complex host responses linked to antiviral defense, inflammation and tissue damage and repair. These processes are increasingly understood to involve systemic metabolic reprogramming. We hypothesized that the liver as a central metabolic hub may orchestrate many of these changes during infection. Thus, we investigated the systemic interplay between inflammation and metabolism in a mouse model of chronic viral infection and hepatitis. Here we show that virus-induced type I interferon (IFN-I) modulates wide-spread metabolic alterations of the liver in a hepatocyte-intrinsic Ifnar1-dependent way. Specifically, IFN-I repressed the transcription of numerous genes with metabolic function including Otc and Ass1, which encode enzymes of the urea cycle. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8 T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation.

immunology↗