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

摘要: Sepsis is a clinical syndrome due to systemic inflammatory response severe microbial infection. High mortality rates in sepsis (200,000/yr the USA) are associated with host’s failure eradicate pathogens lack of neutrophils, excessive pro-inflammatory cytokines, tissue damage and multiple organ failure. While most studies have focused on late consequences sepsis, little known about changes occurring bone marrow (BM) at early stages hematopoiesis how they affect hematopoietic bacterial Using an animal model induced by Pseudomonas aeruginosa, which closely recapitulate lethal burn patients, we previously reported that HSC undergo significant expansion BM block myeloid differentiation. Furthermore, found expanded were unable generate downstream progenitors (common granulocytes/monocytes progenitors) necessary produce had reduced self-renewal. All these effects TLR4-dependent. TLR4 activated LPS signal through two major pathways: TRIF-dependent MyD88-dependent. In this study, show different contribution TLR4-TRIF TLR4-MyD88-dependent pathways aeruginosa LPS. challenge conducted TRIF-null MyD88-null mice demonstrated TRIF was involved pool, but did not play role myelosuppression, whereas MyD88 activation required for LPS-induced suppression. Moreover, impaired engraftment long-term observed wild-type LPS-challenged during transplantation rescued loss function. Taken together, our results indicate distinct theTLR4-TRIF -MyD88 regulation primitive stem/progenitor pool provide insights better understanding molecular mechanisms leading neutropenia. Disclosures: No relevant conflicts interest declare.