Kurzfassung

Bone marrow is the site of generation and central reserve for neutrophil granulocytes (PMN). From here PMN can be mobilized to the circulation and effector sites by diverse stimuli. Generally activated PMN can also cause severe damage, e.g. in the initiation phase of cartilage-destructive diseases such as rheumatoid arthritis. Despite the importance of these issues it is currently not well understood mechanistically, what happens within the bone marrow cavity during the process of PMN...Bone marrow is the site of generation and central reserve for neutrophil granulocytes (PMN). From here PMN can be mobilized to the circulation and effector sites by diverse stimuli. Generally activated PMN can also cause severe damage, e.g. in the initiation phase of cartilage-destructive diseases such as rheumatoid arthritis. Despite the importance of these issues it is currently not well understood mechanistically, what happens within the bone marrow cavity during the process of PMN mobilization or cartilage destruction.
We showed that a major physiologic mobilizer, the cytokine G‑CSF, acts by inducing the motility of PMN within the tibial marrow. This is mediated by increased expression of CXCL1 (KC) and CXCL2 (MIP-2), ligands for CXCR2. Consequently, blocking of CXCR2 inhibits PMN mobilization by G‑CSF. To mimic peripheral inflammation we have used a mouse model overexpressing of IL17A selectively in the skin. Animals present with a phenotype reminiscent of human psoriasis, characterized by infiltration of neutrophils into the skin together with neutrophilia in the bone marrow and bone damage with similarities to osteoporosis. Osteoporosis is a well-known co-morbidity of human psoriasis. We assume that also here the modulation of KC and MIP-2 in the bone and also the skin mediate the observed disease signs.
To mechanistically understand the mobilization of PMN and the IL-17A-mediated psoriasis it is essential to know cellular sources of KC and MIP-2 and their importance under the influence of G-CSF or inflammation. In the first funding phase we generated a novel mouse model with a conditional allele for KC. In addition tdTomato is expressed as a fluorescent reporter from the KC promoter.
Now we plan to complete the generation of an analogous conditional reporter for MIP-2. Both models shall then be analysed during G-CSF-mediated PMN mobilization or IL17A-induced skin inflammation. We will ask which cells and with which kinetics produce KC/MIP-2 in response to the diverse stimuli. Crossing of these mice to defined Cre lines will allow to delete the CXCR2-ligands in a cell type specific manner. This will enable us to clarify, in which cells expression of CXCR2 ligands is decisive for neutrophil recruitment by systemic G-CSF or skin-derived IL17A. The experiments will also allow to clarify how bone loss and joint inflammation are mediated by excess production of KC and MIP-2, either in skin, bone marrow or both. Finally we will continue our ongoing study on the fine structure of the blood vessel system in long bones as a biophysical prerequisite for effective PMN mobilization.
Collectively this study will provide a previously not available knowledge on the physiology and pathophysiology of PMN in the bone marrow and the periphery and the role of CXCR2 for these processes. Together with a comprehensive knowledge on the 3-D structure of the blood vessel network in long bones this lays the groundwork for a central part of cellular osteoimmunology.
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