IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock
| Autor: | Gabrielle Fredman, Julianne N. P. Smith, Katherine C. MacNamara, Jennifer Howard |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Programmed cell death shock Biology HSC Biochemistry Article Mice Interferon Bone Marrow Genetics medicine Animals Progenitor cell Pathogen Receptors Interleukin-18 Bacteria Cell Death Cell Cycle Cell Biology Aplasia Bacterial Infections interferon medicine.disease Hematopoietic Stem Cells cytokines hematopoiesis infection Cell biology Mice Inbred C57BL Haematopoiesis medicine.anatomical_structure Interleukin 18 Female Bone marrow Interferons Protein Kinases IL-18 Developmental Biology medicine.drug Signal Transduction MLKL |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary Severe infection can dramatically alter blood production, but the mechanisms driving hematopoietic stem and progenitor cell (HSC/HSPC) loss have not been clearly defined. Using Ixodes ovatus Ehrlichia (IOE), a tick-borne pathogen that causes severe shock-like illness and bone marrow (BM) aplasia, type I and II interferons (IFNs) promoted loss of HSPCs via increased cell death and enforced quiescence. IFN-αβ were required for increased interleukin 18 (IL-18) expression during infection, correlating with ST-HSC loss. IL-18 deficiency prevented BM aplasia and increased HSC/HSPCs. IL-18R signaling was intrinsically required for ST-HSC quiescence, but not for HSPC cell death. To elucidate cell death mechanisms, MLKL- or gasdermin D-deficient mice were infected; whereas Mlkl−/− mice exhibited protected HSC/HSPCs, no such protection was observed in Gsdmd−/− mice during infection. MLKL deficiency intrinsically protected HSCs during infection and improved hematopoietic output upon recovery. These studies define MLKL and IL-18R signaling in HSC loss and suppressed hematopoietic function in shock-like infection. Graphical abstract Highlights • Type I and II IFNs regulate expression of IL-18 and IL-18R in shock-like infection • IL-18 production contributes to HSC/HSPC loss during shock-like infection • IL-18R signaling in ST-HSCs promotes infection-induced quiescence • MLKL-deficient HSCs are protected during infection MacNamara and colleagues define a cell-autonomous role for IL-18R signaling in enforcing quiescence of ST-HSCs during severe shock-like infection. Analysis of cell death pathways revealed that MLKL was intrinsically required for the profound loss of HSCs during severe infection. IL-18R and/or MLKL targeting during acute infection may preserve hematopoietic function and improve patient outcomes. |
| Databáze: | OpenAIRE |
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