Chemokines play a fundamental role in regulating phagocyte responses during an infection. To test a role of the unusual β chemokine CCL6 in vivo, a mouse model was generated through germline mutagenesis of CCL6. Increased number of bone-marrow cells, myelopoietic activity and enhanced phagocyte recruitment in mutants indicated a regulatory, anti-inflammatory role for CCL6 in vivo, which was suppported by increased chemotaxis of mutant neutrophils to the CCR1 agonist, CCL3/MIP-1α in vitro. Microbiological analysis revealed controlled Listeria monocytogenes infection in both control and mutants. The data presented here is a report on CCL6 deficiency in mice of a mixed background (129xC57BL/6) and 129 congenic background. The importance of background genetics in characterising the role of CCL6 in LPS-induced inflammation became apparent in an in vivo assay for endotoxemia. Upon LPS challenge, CCL6-deficient F2 hybrids produced 30-fold increase in serum TNFα than wild types and succumbed to shock. However, the 129 congenic mice showed increased susceptibility to LPS. A lower expression of CCL6 and linkage to a set of LPS response genes affecting TNFα production and PMN recruitment accounts for the hypersensitivity observed in this background. Despite the effect of background genetics, a contribution of CCL6 in LPS-induced responses was supported by enhanced production of proinflammatory cytokines upon LPS stimulation by macrophages in vitro. Generated by phagocytes themselves, CCL6 regulated hematopoiesis in vivo and also helped sustain the recruitment threshold of phagocytes and CCR1-mediated neutrophil migration via feedback inhibiton. Taken together, the data provides a genetic evidence of the immunomodulatory role of CCL6 in homeostasis and inflammation. Moreover, it provides an in vivo model, the first of its kind, through which the physiological role of the human C6 chemokines may be elucidated.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625204 |
| Date | January 2009 |
| Creators | Mahbub, S. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/17967/ |
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