Hematopoietic stem cells (HSCs) maintain a quiescent state during homeostasis, but with acute
infection, they exit the quiescent state to increase the output of immune cells, the so-called "emergency hematopoiesis." However, HSCs' response to severe
infection during
septic shock and the pathological impact remain poorly elucidated. Here, we report that the
histone demethylase KDM1A/LSD1, serving as a critical regulator of mammalian hematopoiesis, is a negative regulator of the response to
inflammation in HSCs during endotoxic
shock typically observed during acute bacterial or
viral infection.
Inflammation-induced LSD1 deficiency results in an acute expansion of a pathological population of hyperproliferative and hyperinflammatory myeloid progenitors, resulting in a
septic shock phenotype and acute death. Unexpectedly, in vivo administration of bacterial
lipopolysaccharide (LPS) to wild-type mice results in acute suppression of LSD1 in HSCs with a
septic shock phenotype that resembles that observed following induced deletion of LSD1 The suppression of LSD1 in HSCs is caused, at least in large part, by a cohort of
inflammation-induced
microRNAs. Significantly, reconstitution of mice with bone marrow progenitor cells expressing inhibitors of these
inflammation-induced
microRNAs blocked the suppression of LSD1 in vivo following acute LPS administration and prevented mortality from endotoxic
shock. Our results indicate that LSD1 activators or
miRNA antagonists could serve as a therapeutic approach for life-threatening
septic shock characterized by dysfunction of HSCs.