Intracellular processing of receptor signalling towards functional output in terms of gene expression or behaviour is key to the plasticity of immune cells. Project area B unites projects that aim at understanding how intracellular processing of signals regulates neutrophil function. Specifically, the projects cover the rearrangement of the actin cytoskeleton, the importance of nuclear receptors and transcription factors for gene expression, as well as the ability of neutrophils and their progenitors to be trained.
B1: Studying inborn errors of immunity affecting neutrophil granulocytes (Christoph Klein)
The recruitment and host defence functions of neutrophil granulocytes critically depend on the tightly controlled reorganization of the actin network. In our discovery pipeline for children with inborn errors of immunity, we recently identified novel genetic variants in three actin-regulatory genes: FSCN, MIGFILIN, and ARHGEF6. The clinical phenotypes are variable, ranging from neutropenia to a hyper-inflammatory syndrome. In the present proposal we aim to identify the molecular and cellular pathophysiological mechanisms underlying these newly defined inborn errors of immunity.
B2: Neutrophil modulation during cerebral ischemia by the nuclear receptor NR4A1 (Luisa Klotz & Jens Minnerup)
Sterile inflammation upon cerebral ischemia is accompanied by immune cell infiltration. Neutrophils exert a crucial role within the inflammatory response and finally on neuronal damage via interaction with other immune cells of the innate and adaptive immune system. However, unselective blockade of brain neutrophil infiltration has so far been unsuccessful in clinical studies. We hypothesize that neutrophils are differentially modulated in the context of stroke, that the nuclear receptor NR4A1 is critically involved and that pharmacological modulation of NR4A1 opens the possibility of a fine-tuned therapeutic intervention.
B3: Neutrophil-intrinsic control of immune activity (Frank Rosenbauer)
Because neutrophils operate with poor target precision, their activity must be tightly controlled. Recently, we showed that the transcription factor PU.1 shields the chromatin from indiscriminate transcriptional activity, thus safeguarding neutrophils from carrying out an inappropriate immune response. Yet, how neutrophils overcome this PU.1-instructed ‘chromatin barrier’ in infectious situations remains unexplored. Hence, we will here study epigenetic mechanisms operating in neutrophils to fine-tune their activity states during infection and inflammation.
B4: Dissecting the anti-tumour effects of trained neutrophils (Triantafyllos Chavakis)
Neutrophils exert both pro- and anti-tumour activities. A frequent scenario in cancer is that tumours hijack granulopoiesis resulting in a tumour-promoting neutrophil phenotype. Trained innate immunity indicates that some stimuli can induce, via epigenetic rewiring, long-term functional changes in myeloid cells and their progenitors, leading to an increased reaction upon exposure to a secondary challenge. Here we will dissect how innate immune training of granulopoiesis and neutrophils promotes anti-tumour activity. Our work will establish innate immune training of neutrophils as a novel adjuvant tumour immunotherapy.
B5: Innate immune memory of neutrophils during inflammation (Johannes Roth)
Molecular pathways underlying neutrophil diversity remain ill-defined. In this project we will follow the hypothesis that mechanisms of innate immune memory prime the functional phenotype of neutrophils regarding their subsequent response patterns; a process which may be relevant during development of myeloid stem cells as well as during repetitive stimulation of mature (sub)-populations of neutrophils. The long-term goal of our project is the targeted manipulation of innate immune memory mechanisms in neutrophils for treatment of inflammatory diseases.