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Cell Journal، جلد ۱۵، شماره Suppl ۱، صفحات ۷-۷
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عنوان انگلیسی Is-17: Impact of TLR-Agonists on Hematopoietic Stem Cell Homeostasis
چکیده انگلیسی مقاله Objective: Systemic bacterial infection triggers inflammatory responses, as exemplified by septic shock. While humoral mediators and mature hematopoietic cell reactions are well studied in this process, little is known about respective responses in immature hematopoietic cells in the bone marrow (BM). We have previously shown that short-term repetitive injection of lipopolysaccharide (LPS), a gram negative bacterial component, induces proliferation of dormant hematopoietic stem cells (HSCs) in BM that retain lifelong self-renewal and multi-lineage differentiation. Here we examine the underlying molecular pathways as well as cellular function of HSCs upon chronic LPS challenge. Materials and Methods: Genetically modified mice which lack toll-like receptor 4 (TLR) or downstream signal molecules have been used to generate BM chimeric mice and were challenged with LPS purified from E. coli. 0111:B4. Results: To dissect if TLR4 ligation by LPS leads to direct or indirect activation of HSCs, we generated mixed BM chimeric mice by reconstituting wild-type (WT) recipients with WT and Toll-like receptor 4 deficient (TLR4 KO) cells in a 1:1 ratio followed by systemic injection of PBS or LPS. Monthly peripheral blood analysis showed that in animals chronically challenged with LPS, TLR4 KO cells outcompeted WT cells in all lineages, while PBS treated controls maintained a 1 to 1 chimerism. The same result was observed when TLR4KO recipient mice were used. Secondary transplantation showed continuous decline in hematopoietic contribution of WT cells. These data demonstrate that direct activation of TLR4 on HSCs limits their competitive repopulating ability.In mature immune cells TLR4 ligation by LPS activates two downstream pathways mediated by two proximal adaptor molecules, MYD88 and TRIF. To determine the respective pathways active in HSCs, we utilized TRIF and MYD88 KO mice. Acute LPS challenge induced up-regulation of Sca-1 expression and thus numeric expansion of immunophenotypically defined HSC populations in WT mice. This effect was absent in TRIF KO but not in MYD88 KO mice. Consistent with phenotypic changes, TRIF KO HSCs, similar as TLR4 KO HSCs, retained a competitive repopulating advantage over WT cells upon LPS stimulation, while this was not observed in MYD88 KO HSCs. However, the lack of response to LPS in TRIFKO is not due to general cellular unresponsiveness, as Pam3CSK4, a ligand for TLR1/2 causes both phenotypic expansion and dysfunction in TRIFKO HSCs. Furthermore, we observed rapid activation of reactive oxygen species (ROS) and p38 (mitogen activated protein kinase 14) in HSCs after in vivo LPS stimulation. Pharmacological inhibition of both molecules blocked phenotypic HSC (LKS) expansion in acutely LPS-treated mice, and rescued HSC from LPS-induced dysfunction in competitive repopulation experiments. In contrast, analysis of mature hematopoietic cells showed that early expansion of immature granulocytes in response to LPS was abrogated in MYD88 KO mice, while WT, TRIF KO, and WT mice treated with ROS/p38 inhibitors retrained this response, indicating that emergency granulopoiesis is dependent on TLR4-MYD88 signaling. Conclusion: Our findings demonstrate that LPS directly acts on TLR4 expressed on HSC in BM and causes functional impairment through TRIF-ROS-p38 signaling pathways. Thus, specific blockage of TRIF-ROSp38 or further downstream signals during inflammation might allow to prevent HSCs from functional exhaustion, while preserving at least short-term production of granulocytes for an efficient innate immune response against pathogens.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/782
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