Together we are stronger: Adrenal hormones in concert orchestrate the resolution of inflammation

• Applicant: Privatdozentin Dr. Sabine Vettorazzi
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537908488

Repair processes and restoring tissue homeostasis are active and coordinated integral components for the resolution of inflammation that are mediated among others by macrophages (mph). Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) and are widely prescribed drugs to combat inflammatory disease like rheumatoid arthritis, allergies, acute lung injury and support the resolution of inflammation. However, their beneficial anti-inflammatory effects are accompanied by severe adverse effects (diabetes, liver steatosis, osteoporosis, muscle atrophy etc.) due to their systemic action. Not only GCs, but also catecholamines, as adrenal gland hormones, support the resolution of inflammation by reducing inflammatory cytokine release and attenuate acute lung injury by acting through the beta-adrenergic receptor 2 (Adrb2). The project aims to understand the interaction of GR and Adrb2 in mph to enhance resolution of inflammation on a cellular and molecular level. It is of therapeutic relevance to induce only a local resolution of inflammation, enhance resolving process by a cell-based therapy and therefore avoid both systemic immune suppression and GC-induced side effects. In a pulmonary disease model we will exploit the combined effects of GCs and catecholamines with a main focus on mph and other lung cell populations. By using single nuclei (sn) ATACseq (profiling DNA’s accessibility) and simultaneous snRNA expression analysis (snRNAseq) via multiome assay we will link cell type specific GR and Adrb2 binding to cell type specific GC and catecholamine responses on the gene level in the lung. Especially in mph we will be able to understand fundamental mechanisms for the interaction of GCs and catecholamines by providing the first GR cistrome (ChIP-seq), a road-map of GC and catecholamine mediated gene regulation and translocation as well as mph polarization assays. Moreover, the clearance of apoptotic cells is a key process for the resolution of inflammation and hence to regain tissue homeostasis. Therefore, we will investigate the GR and Adrb2 interaction in peritoneal mph (PMs) during peritonitis with focus on efferocytosis and examine PM transcriptome and protein phosphorylation status. The aim is to identify decisive inflammation resolving proteins induced by GCs and catecholamines. By integrating data from Adrb2fl/fl and GRfl/fl conditional myeloid knockout mice (LysMCre+), we will clarify if the Adrb2 needs the GR for its resolving effects. At the end, the efferocytosis deficiency of the conditional knockout mice will be rescued with recombinant proteins identified by the transcriptome and phospho-protein-array. All murine findings will be verified in primary human Mph from healthy donors under inflammatory and non-inflammatory conditions. We plan to provide a novel combined treatment strategy, high quality snRNA-/snATACseq and GR ChIP-seq reference datasets to the scientific community as a therapeutic intervention in inflammatory diseases.

• DFG Programme: Research Grants