Project Details
Projekt
Analyses of murine neutrophil granulocyte steady-state homeostatic regulation
Applicant
Dr. Stefanie Bugl
Subject Area
Hematology, Oncology
Term
from 2014 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 263717212
Polymorphonuclear neutrophil granulocytes represent the first line of immune response against invading pathogens and are part of the inborn immunity. Neutrophil numbers are tightly controlled by an incompletely understood homeostatic feedback loop, which adjusts the bone marrows supply to peripheral needs. The expected results in this proposal contribute to a better understanding of the homeostatic regulation of neutrophils. In her thesis, the applicant showed that a possible sensor in the regulation of neutrophil homeostasis relies on highly conserved pattern recognition receptors indirectly sensing the consequences of reduced neutrophil levels. The positive feedback loop was found to be independent of lymphocytes, commensal bacteria and the adaptor protein MyD88. Instead, the above-mentioned phenomena are dependent on TLR4/TRIF signalling. The results were published as plenary paper in Blood, 2013. In this proposal further questions shall be clarified: the identity of the TLR4-positive sensor and the compartment that triggers TLR4. Furthermore it is unknown which cell type produce the major amount of G-CSF (causal for the feedback-loop). Using the Genista-mouse model we want to analyze genetically modified neutropenic mice to characterize their neutrophil homeostasis. Genista-mice have a nearly complete loss of mature neutrophil granulocytes. Both the effect of the intestinal flora on regulation of neutrophils and also the effect of different lipopolysaccharide (LPS) structures on the generation and release of neutrophils from the bone marrow has not been examined in detail. The expectable results can provide hints, if changes in the intestinal flora contribute to neutropenia or adverse effects of chemotherapy. Preliminary data show that in C57BL/6 wild type mice the number of neutrophils in the peripheral blood is dependent on treatment with different LPS structures in their drinking water. This data suggests that in fact there is a correlation between neutrophil numbers and the intestinal flora, a continuum that deserves further investigation.
DFG Programme
Research Grants
International Connection
France
