It is likely that the hematopoietic response to infection is mediated in large part by the indirect effects of inflammatory mediators produced following TLR-mediated microbial detection by differentiated cells (hematopoietic and nonhematopoietic). However, the findings described above shift the paradigm
of microbial detection exclusively by differentiated cells, and demand a reexamination of the role of TLRs in immune responses to include specific evaluation of their involvement in instructing immune cell development following direct detection of microbes and their components by HSPCs. HSPC activation certainly can occur in response to many stimuli, including growth and Smoothened Agonist differentiation factors, inflammatory cytokines, and microbial
components, as well as potentially to endogenous “danger signals” produced during infection or tissue damage. Each of these stimuli may have a relatively greater or lesser impact under specific physiological conditions (during homeostasis, or upon emergency myelopoiesis during inflammation or infection). It will therefore be extremely important to determine how HSPCs integrate multiple signals, from independent and/or partially overlapping pathways, to orchestrate the differentiation of specific hematopoietic populations under normal physiologic and pathophysiologic conditions. For instance, it has been reported that TLR signaling can influence GM-CSF-driven DC production BGB324 by BM progenitors in vitro, and that different TLRs have distinct effects. Ligands for TLR4 and TLR9 drive the production of pDCs, whereas influenza viruses and TLR3 ligands reduce DC
production but increase neutrophil generation . The functional properties of the myeloid cells produced also likely depend on the specific molecular composition of the pathogen (i.e. the combination of PRRs triggered) and the nature of the other myelopoietic signals the HSPCs receive. This might permit fine-tuning of emergency myelopoiesis to tailor the response to more effectively deal with a specific infection. Conversely, it is possible that some pathogens have evolved mechanisms to modulate HSPC responses in order to evade the immune system. Examination of the function of the myeloid cells produced by HSPCs PI-1840 following TLR ligation is, therefore, also critical. Indeed, in vitro TLR ligation on HSPCs has been reported to modulate their chemokine receptor expression, and consequently favors HSPC migration to inflammatory/infection sites, indicating that TLRs also regulate HSPC trafficking [6, 48]. Moreover, we recently showed that macrophages produced by HSPCs exposed to the TLR2 agonist Pam3CSK4 either prior to or during differentiation (in vitro and using an in vivo transplantation approach as described above) exhibit reduced inflammatory cytokine and reactive oxygen responses .