Activation Of TLR4-MyD88 Pathway Impairs HSC Function During Acute Inflammation

Sepsis is a clinical syndrome due to a systemic inflammatory response to severe microbial infection. High mortality rates in sepsis (200,000/yr in the USA) are associated with the host’s failure to eradicate pathogens due to the lack of neutrophils, excessive pro-inflammatory cytokines, tissue damage and multiple organ failure. While most studies have focused on the late consequences of sepsis, little is known about the changes occurring in the bone marrow (BM) at early stages of hematopoiesis and how they affect the hematopoietic response to bacterial infection. Using an animal model of severe sepsis induced by Pseudomonas aeruginosa, which closely recapitulate lethal sepsis in burn patients, we have previously reported that HSC undergo a significant expansion in the BM associated with a block of myeloid differentiation. Furthermore, we found that expanded HSC were unable to generate the downstream progenitors (common myeloid progenitors and granulocytes/monocytes progenitors) necessary to produce neutrophils, and had reduced self-renewal. All these effects were TLR4-dependent. TLR4 is activated by bacterial LPS and signal through two major pathways: TRIF-dependent and MyD88-dependent. In this study, we show the different contribution of the TLR4-TRIF and the TLR4-MyD88-dependent pathways to the BM response to Pseudomonas aeruginosa LPS. LPS challenge conducted on TRIF-null and MyD88-null mice demonstrated that TRIF was involved in the expansion of the HSC pool, but did not play a major role in the myelosuppression, whereas MyD88 activation was required for LPS-induced myeloid suppression. Moreover, we found that the impaired engraftment at long-term observed in wild-type LPS-challenged HSC during transplantation was rescued by MyD88 loss of function. Taken together, our results indicate a distinct role of theTLR4-TRIF and -MyD88 pathways in the regulation of the primitive stem/progenitor pool during sepsis and provide insights for a better understanding of the molecular mechanisms leading to neutropenia.