Project Area C: Neutrophil response

The functional output of neutrophils including their recruitment to tissues, their extrusion of NETs and their death and subsequent clearance is of primary importance for the design of therapeutic interference strategies. Hence, projects defined in project area C will not just reveal refined understanding of neutrophil function but also provide a translational link with assessment of preclinical intervention approaches some of which are consolidated by the integration of analyses of patient samples. In addition, we will implement preclinical randomized controlled bi-/multi-centre trials on disease models available in more than one partner sites including stroke and arthritis models.

 

 

C1: The role of the phosphatases CD45 and CD148 in the onset and progression of rheumatoid arthritis (Alexander Zarbock)
Rheumatoid arthritis (RA) is an systemic autoimmune disorder characterized by chronic inflammation and synovial infiltration of immune cells. In the arthritic joint, neutrophils are the most abundant population. Phosphatases, and in particular CD45 and CD148, are key molecules in the regulation of neutrophils at the site of inflammation. This study will shed light on how CD45 and CD148 drive leukocyte recruitment during the different phases of arthritis and may hence lay the foundation for a therapeutic approach modulating neutrophil infiltration.

C2: The role of KV1.3 on Ca2+ signalling and neutrophil effector functions (Markus Sperandio)
Neutrophils play a critical role during the inflammatory response. Recent studies have demonstrated that loss of the voltage-gated potassium channel KV1.3 impairs sustained calcium signalling during neutrophil activation leading to impaired phagocytosis and neutrophil adhesion. Here we aim to dissect the exact role of KV1.3 in neutrophil functionality with specific focus on neutrophil recruitment, NET release and inflammasome activation.

C3: Host-pathogen interactions in neutrophils (Daniela Maier-Begandt & Barbara Walzog)
In this proposal, we will decipher the role of coronin 1A (CORO1A) and its interacting partner secretory carrier-associated membrane protein 3 (SCAMP3) for pathogen escape strategies in neutrophils upon infection with Helicobacter pylori and Mycobacterium species. As these pathogens recruit CORO1A to their intracellular niche, we will study how CORO1A and SCAMP3 may be hijacked by these pathogens to circumvent host defence. The identification of these molecular mechanisms may improve our understanding of neutrophil-dependent pathogen escape strategies and can lead to the development of novel therapeutic concepts.

C5: Phagocytic crosstalk between neutrophils and macrophages in rheumatoid arthritis (Noelia Alonso Gonzalez & Annika Grüneboom)
During the inflammatory response in Rheumatoid Arthritis (RA), neutrophils show targeted migration towards distinct anatomical niches, such as the synovial cavity and the synovial fat pad, also populated by heterogeneous macrophage populations. There, neutrophils undergo different cell death modalities, apoptosis and NETosis. We hypothesize that neutrophil subpopulations individually drive RA pathogenesis through their clearance by macrophages. Hence, our studies will provide valuable information on neutrophil-driven macrophage inflammatory responses, focusing on the effects of neutrophil cell death in macrophages.

C6: The role of Ly6g and CD177 as “eat me” signals to control neutrophil-mediated tissue destruction in stroke (Matthias Gunzer & Dirk Hermann)
Among murine leukocytes neutrophils exclusively express high levels of Ly6G. The human analogue, CD177, is lacking on neutrophils in ~5% of the general population. However, the functional role of both molecules remains unknown. In this project, we will investigate the hypothesis that Ly6G/CD177mediates the phagocytosis of brain-infiltrating neutrophils through microglia. By elucidating the underlying mechanisms, we aim to identify means for its selective therapeutic modulation in stroke. In a clinical setting we will investigate the importance of CD177 for the outcome and future clinical management of human stroke.

C7: Role of S100A8/A9 dimers and tetramers in the regulation of neutrophil dynamics in chronic inflammation (Sven Hermann & Thomas Vogl)
The aim of the present proposal is to understand how neutrophils are controlled to prevent un-wanted immune system activation. We hypothesize that S100A8/A9 with its two occurring quaternary structures dimer versus tetramer differentially modulate neutrophils, with tetramers keeping them in a silent but alert mode upon dimer activation, thereby locally confining neutrophil activity. A better understanding of these regulatory mechanisms and how they can be tuned will pave the way towards novel therapeutic interventions in chronic inflammatory neutrophil-driven diseases.