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

Abstract

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.

Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization

“…Flow cytometric staining was performed as previously described ( Howard et al., 2021 ). Spleen and whole BM, flushed from femurs and tibias, were processed and then filtered through a 70 μm filter.…”

Innate Lymphoid Cell Plasticity in Mucosal Infections

“…IL-18R expression has been detected in bone-marrow progenitor cells [ 151 , 152 ]. Furthermore, IL-18 produced during inflammation can reduce hematopoietic stem cell differentiation [ 152 , 153 ].…”

“…IL-18R expression has been detected in bone-marrow progenitor cells [ 151 , 152 ]. Furthermore, IL-18 produced during inflammation can reduce hematopoietic stem cell differentiation [ 152 , 153 ]. Additionally, a recent work suggests that IL-18R signaling is dispensable for ILC development but inhibits differentiation of ILCPs [ 151 ].…”

The role of inflammation in hematopoiesis and bone marrow failure: What can we learn from mouse models?

“…Additional work has also shown that IFNα/β is required for the increase of IL-18 expression during infection processes leading to loss of short-term HSCs. Absence of IL-18 was shown to prevent BM aplasia and increase HSCs/HSPCs ( 125 ).…”