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| Item Type: | Article |
|---|---|
| Title: | A complex proinflammatory cascade mediates the activation of HSCs upon LPS exposure in vivo |
| Creators Name: | Demel, U.M., Lutz, R., Sujer, S., Demerdash, Y., Sood, S., Grünschläger, F., Kuck, A., Werner, P., Blaszkiewicz, S., Uckelmann, H.J., Haas, S. and Essers, M. |
| Abstract: | Infections are a key source of stress to the hematopoietic system. While infections consume short-lived innate immune cells, their recovery depends on quiescent hematopoietic stem cells (HSCs) with long-term self-renewal capacity. Both chronic inflammatory stress and bacterial infections compromise competitive HSC capacity and cause bone marrow failure. However, our understanding of how HSCs act during acute and contained infections remains incomplete. Here, we used advanced chimeric and genetic mouse models in combination with pharmacological interventions to dissect the complex nature of the acute systemic response of HSCs to lipopolysaccharide (LPS), a well-established model for inducing inflammatory stress. Acute LPS challenge transiently induced proliferation of quiescent HSCs in vivo. This response was not only mediated via direct LPS-TLR4 conjugation on HSCs, but also involved indirect TLR4 signaling in CD115+ monocytic cells, inducing a complex pro-inflammatory cytokine cascade in the bone marrow. Downstream of LPS-TLR4 signaling, the combined action of pro-inflammatory cytokines such as IFNα, IFNγ, TNFα, IL-1α, IL-1β and many others is required to mediate full HSC activation in vivo. Together, our study reveals detailed mechanistic insights into the interplay of proinflammatory cytokine-induced molecular pathways and cell types that jointly orchestrate the complex process of emergency hematopoiesis and HSC activation upon LPS exposure in vivo. |
| Keywords: | Cytokines, Hematopoiesis, Hematopoietic Stem Cells, Lipopolysaccharides, Toll-Like Receptor 4, Animals, Mice |
| Source: | Blood Advances |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Volume: | 6 |
| Number: | 11 |
| Page Range: | 3513-3528 |
| Date: | 10 June 2022 |
| Official Publication: | https://doi.org/10.1182/bloodadvances.2021006088 |
| PubMed: | View item in PubMed |
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