IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock

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. [Display omitted] •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.