Abstract:
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.
