| First Author | Howard JE | Year | 2021 |
| Journal | Stem Cell Reports | Volume | 16 |
| Issue | 12 | Pages | 2887-2899 |
| PubMed ID | 34798063 | Mgi Jnum | J:317682 |
| Mgi Id | MGI:6854108 | Doi | 10.1016/j.stemcr.2021.10.011 |
| Citation | Howard JE, et al. (2021) IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock. Stem Cell Reports 16(12):2887-2899 |
| abstractText | 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-alphabeta 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. |
