Role of chemokine receptors in inflammation-induced haematopoietic progenitor cell mobilisation

Q Science (General);RZ Other systems of medicine

Adu, Patrick ; Graham, Gerard J.

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: Chemokines, chemokine receptors, haematopoietic progenitor cells;   

Others  :  http://theses.gla.ac.uk/5866/1/2014AduPhD.pdf

来源: University of Glasgow

【 摘 要 】

Background: There is a high cellular turnover in the haematopoietic system which necessitates that new cells are continuously produced to replace old and senescent ones. The haematopoietic stem cells and its progenitors meet this requirement. In adults, haematopoietic stem and progenitor cells (HSPCs) generally occupy a unique microenvironment in the bone marrow called the niche. However, recent findings have shown that approximately 0.06% of HSPCs circulate between bone marrow and periphery in steady state. Evidence shows that HSPC express cytokine receptors and pathogen recognition receptors [e.g. Toll-like receptors (TLRs)], which suggest that HSPCs may directly respond to inflammation and infection. The capacity of HSPCs to directly respond to infection is demonstrated in models of bacterial infection using LPS injection that significantly increases the number of circulating HSPCs. However, the underlying mechanism is not clearly understood. As chemokines orchestrate in vivo cellular migration, it was hypothesised that HSPC inducibly express inflammatory chemokine receptors that enable them to respond to circulating chemokines during infection and inflammation. Methods and results: Here, the impact of systemic or peripheral inflammation on HSPC of mice was investigated using LPS injection and topical imiquimod cream/TPA treatment respectively. Using haematopoietic progenitor colony-forming assays, RT-QPCR on isolated progenitors, gene-knockout mice, flow cytometric analysis and in vivo antibody-mediated neutralisation experiments, data are provided showing that HSPC inducibly express chemokine receptors in response to inflammation. Critically, the topical imiquimod inflammation model required functional chemokine receptor 2 (Ccr2) for HSPC mobilisation in contrast to both systemic LPS and topical TPA models, which were Ccr2-independent. Furthermore, dermal inflammation was necessary for imiquimod-mediated HSPC mobilization, as subcutaneously administered imiquimod did not result in significant HSPC mobilization. Conclusion: The data suggest that, in addition to the established CXCR4-CXCL12 axis that regulates homeostatic HSPC trafficking, the inflammatory chemokine-chemokine receptor axes may also be crucial in modulating HSPC functions during infection and inflammation.