IFN alpha signaling drives hematopoietic stem cells malfunction under acute inflammation.

Inflammation stimulation regulates the activity of hematopoietic stem cells (HSCs) through direct-sensing and cytokine-mediation. It is known that HSCs directly sense lipopolysaccharide (LPS), a classical infection-related inflammatory signal, via toll like receptor 4 (TLR4) and subsequently become active. However, the mechanism underlying the activity change of HSCs induced by LPS remains incompletely disclosed. Here we explored that under LPS stimulation, the activation of interferon alpha (IFNα) signal pathway resulted in the activation and exhaustion of HSCs in vitro, indicating HSCs directly responded to LPS through the downstream IFNα signal pathway. We also discovered the increased production of IFNα in mice bone marrow and expression of interferon-α/β receptor (IFNAR) on mice HSCs after LPS stimulation. Creatine, an IFNα inhibitor, could reverse the activation and prevent the exhaustion of HSCs caused by LPS by suppressing the expressions of genes associated with the IFNα signal pathway both in vitro and in vivo. Furthermore, we found that the IFNAR deficiency in mice effectively protected HSCs from activation, elevated apoptosis and impaired reconstitution ability under LPS stimulation in vivo. This finding further supports the notion that LPS activates and injures HSCs indirectly via promoting IFNα secretion in the bone marrow environment. Overall, our findings reveal that LPS causes the injury to HSCs either through direct or cytokine-mediated indirect activation of the IFNα signal pathway.