Low density neutrophils in inflammaotry diseases and aggregated NETs as supporters for the resolution of inflammation
Head: Dr. rer. nat. Christine Schauer (née Schorn)
We are concerned with neurophils, in particular with one of their defense mechanisms, neutrophil extracellular traps (NETs). In high concentrations, NETs tend to aggregate and can affect various immune reactions. Aggregated NETs not only occlude vessels and glands, they also bind inflammatory cytokines and degrade them. In this way, they support the resolution of inflammation.
We are also investigating these pro- and anti-inflammatory properties of NETs with respect to a specific subpopulation of neutrophils.
The so-called "low density neutrophils" (LDNs), in contrast to neutrophils with normal density, reside in the upper cell layer after density gradient centrifugation. This cell population is described to be particularly inflammatory in patients with systemic lupus erythematosus due to increased cytokine and NET release. We are interested in the origin of this neutrophil population and its impact on the pathogenesis of various inflammatory diseases.
- "Low density" neutrophils in inflammatory diseases.
"Low density" neutrophils (LDNs) were first described in Systemic Lupus Erythematosus (SLE). They are present in the upper cell layer after density gradient centrifugation, which led to their name. LDNs in patients with SLE are known to increasingly release inflammatory cytokines and neutrophil extracellular traps (NETs), thereby influencing disease pathology. We are investigating the presence of LDNs not only in patients with SLE, but also in other inflammatory diseases, including Covid-19. Some patients suffering from Covid-19 show elevated levels of LDNs. We are investigating the correlations between the presence of these cells and various clinical parameters, including overall disease progression, ICU hospitalization, and the need for ventilation. In addition, we are interested in determining the properties of these cells, such as the tendency to form NETs, release of cytokines, mobility, and platelet binding. Our goal is to understand the role of LDNs in various inflammatory diseases in order to counteract potential exaggerated inflammation.
- In vitro generation of "low density" neutrophils
The origin of LDNs is still largely unknown. Therefore, we are interested not only in determining the pro- and anti-inflammatory properties of the cells, but also in better understanding their formation. We have been able to detect LDNs at different stages of maturation from patient samples, indicating that lower density neutrophils might also be produced in the case of neutropenia.
On the other hand, we are able to generate LDNs in vitro by stimulation. Taken together, this suggests a wide heterogeneity in the population. Our goal is to better understand the origin of LDNs using different stimuli. In addition, we are investigating different activation features of neutrophils and their role in density changes.
- Aggregated NETs contribute to the resolution of inflammation
Aggregation of NETs can lead to the occlusion of various vessels and glands. This can cause organ damage and eventually death, highlighting the harmful effects of aggregated NETs (aggNETs). However, aggNETs can also trap and neutralize inflammatory mediators such as cytokines. These become entangled in NET born DNA fibbers, which are particularly prevalent after aggregation. The cytokines are degraded at these DNA-bound enzymes, such as neutrophil elastase or myeloperoxidase. In this way, aggNETs not only contribute to harmful vascular occlusion, but also play an important role in the resolution of inflammation. We are investigating both the formation and the deleterious and anti-inflammatory properties of aggNETs in different pathologies.
| Christine Schauer (née Schorn) | Junior Research group leader |
| Aparna Mahajan | Postdoctoral researcher |
| Janina Schoen | Scientific doctoral student |
Deutsche Forschungsgemeinschaft (DFG)
Single application "Neutrophil extracellular traps form the nidus of human gall stones." (since 2016)
ELAN-Program, Friedrich-Alexander University Erlangen-Nürnberg
P032 - „Imaging of inflammation and bone remodeling in vivo.“ (2018-2020)
IZKF First-time applicant, Universitätsklinikum Erlangen
J41 - „Neutrophil-induced limitation of inflammation in gouty arthritis." (2013-2016)
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- Podolska MJ, Mahajan A, Hahn J, Knopf J, Maueröder C, Petru L, Ullmann M, Schett G, Leppkes M, Herrmann M, Muñoz LE, Schauer C. (2019) Treatment with DNases rescues hidden neutrophil elastase from aggregated NETs. J Leukoc Biol. 106(6):1359-1366. Epub 2019 Sep 2.
- Muñoz LE*, Boeltz S*, Bilyy R*, Schauer C*, Mahajan A, Widulin N, Grüneboom A, Herrmann I, Boada E, Rauh M, Krenn V, Biermann MHC, Podolska MJ, Hahn J, Knopf J, Maueröder C, Paryzhak S, Dumych T, Zhao Y, Neurath MF, Hoffmann MH, Fuchs TA, Leppkes M, Schett G, Herrmann M. (2019) Neutrophil Extracellular Traps Initiate Gallstone Formation. Immunity. 51(3):443-450.e4. Epub 2019 Aug 15. *equally contributed
- Hahn J*, Schauer C*, Czegley C, Kling L, Petru L, Schmid B, Weidner D, Reinwald C, Biermann M, Blunder S, Ernst J, Lesner A, Bäuerle T, Palmisano R, Christiansen S, Herrmann M, Bozec A, Gruber R, Schett G, Hoffmann MH. (2019) Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases. FASEB J. 33(1): 1401–1414. Epub 2018 Aug 21. *equally contributed
- Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, Lell M, Manger B, Rech J, Naschberger E, Holmdahl R, Krenn V, Harrer T, Jeremic I, Bilyy R, Schett G, Hoffmann M, Herrmann M. (2014) Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 20(5):511-7. Epub 2014 Apr 28.
- Schorn C, Janko C, Krenn V, Zhao Y, Munoz LE, Schett G, Herrmann M. (2012) Bonding the foe – NETting neutrophils immobilize the pro-inflammatory monosodium urate crystals. Front Immunol. 3:376. eCollection 2012.
- Schorn C, Janko C, Latzko M, Chaurio R, Schett G, Herrmann M. (2012) Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells. Front Immunol.3:277. eCollection 2012.
- Schorn C, Frey B, Lauber L, Janko C, Strysio M, Keppeler H, Gaipl US, Voll RE, Springer E, Munoz LE, Schett G, Herrmann M. (2011) Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem. 286(1):35-41. Epub 2010 Nov 4.
- Schorn C, Strysio M, Janko C, Munoz LE, Schett G, Herrmann M. (2010) The uptake by blood-borne phagocytes of monosodium urate is dependent on heat-labile serum factor(s) and divalent cations. Autoimmunity. 43(3):236-8.
- Schorn C, Janko C, Munoz L, Schulze C, Strysio M, Schett G, Herrmann M. (2009) Sodium and potassium urate crystals differ in their inflammatory poential. Autoimmunity. 42(4):314-6.