TRR 332 – Neutrophils: Origin, Fate & Function

Neutrophils are the most common white blood cells in human blood. Among other functions, they play a central role in chronic inflammation and tumour diseases. The Collaborative Research Centre Transregio 332 »Neutrophils: Origin, Fate & Function « investigates the diverse mechanisms that regulate their behaviour. The focus is on how the immediate environment of neutrophils – for example, in tumours or inflamed tissue – influences their response, which intracellular signalling pathways regulate their functions, and what role they play in various diseases. The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) is funding the consortium with around 13 million euros for a second funding period running until 2030. The goal is to translate new findings into clinical practice and, in the long term, to develop new therapeutic approaches. ISAS is participating with two subprojects.

Immune cell interaction in rheumatoid arthritis

Rheumatoid arthritis is one of the most common autoimmune diseases. This chronic joint inflammation occurs when the body’s own immune cells attack the tissue. However, the mechanisms that trigger this autoimmune disease are not yet fully understood. In the sub-project »Functional macrophage modulation via neutrophils in inflammatory arthritis», researchers at ISAS (led by Prof. Dr Anika Grüneboom and Dr Ricardo Grieshaber-Bouyer from Universitätsklinikum Erlangen) are analysing the role of neutrophils in this disease. The scientists are investigating how immune cells of the type of phagocytes – specifically neutrophils and macrophages – communicate with one another, and how this cellular crosstalk influences inflammatory processes and disease progression in rheumatoid arthritis. Their objective: to characterise distinct functional subtypes of neutrophils with respect to their roles in both the initiation and chronic progression of joint inflammation. With these analyses, the scientists aims to identify novel therapeutic targets for the treatment of inflammatory rheumatic diseases.

Regulation of neutrophil subtypes for new therapeutic approaches

Using multimodal imaging techniques such as light-sheet fluorescence microscopy and confocal microscopy, the scientists are investigating the functions these subpopulations perform within their respective tissue niches and the role they play in the development of the disease. Flow cytometry and spatial transcriptomics analyses are also being employed in this research. Establishing the latter sequencing analysis on bone tissue presents a methodological challenge, as there is currently no standardised protocol for this worldwide. Their investigations include samples from both mice and human tissue.

Analysis of neutrophils using OrgaAIPlexing

Neutrophils possess a complex internal cellular architecture. Various organelles, such as mitochondria, the endoplasmic reticulum and the Golgi apparatus, perform different functions and collectively influence cellular activity. ISAS researchers led by Dr Jianxu Chen and scientists with Dr Angelika Rambold from the University of Münster are investigating how individual organelles interact in neutrophils as part of the sub-project “Deciphering the Structural Code of Neutrophil Metabolism and Function.”

To visualise the functional interaction between organelles, OrgaAIPlexing is used, an integrated approach that combines imaging, artificial intelligence and molecular measurement techniques. This method enables simultaneous detection of changes across multiple organelles and allows their activity to be visualised within the cellular context. Originally developed for macrophages, the approach is now being adapted for neutrophils. To this end, the team is establishing a specialised research platform that integrates multispectral imaging, AI assisted segmentation, and computer-aided modelling. Their aim is to systematically quantify the characteristics of the organelles, identify typical patterns using machine learning, and visualise differences between cell types and states of activation.

The findings from these sub-projects are expected to contribute to the development of novel therapeutic strategies, for example in rheumatoid arthritis, based on the targeted regulation of neutrophil subtypes.