Over one million newborns die annually from
sepsis with the highest mortality in premature and low-
birthweight infants. The
inflammasome plays a central role in the regulation of innate immunity and
inflammation, and is presumed to be involved in protective immunity, in large part through the caspase-1-dependent activation of interleukin-1β (IL-1β) and
IL-18. Studies in endotoxic
shock, however, suggest that endogenous caspase-1 activity and the
inflammasome contribute to mortality primarily by promoting excessive systemic inflammatory responses. We examined whether caspase-1 and the
inflammasome also regulate neonatal
inflammation, host protective immunity and myelopoiesis during polymicrobial
sepsis. Neonatal (5-7 days) C57BL/6 and
caspase-1/11(-/-) mice underwent a low-lethality caecal slurry model of intra-abdominal
sepsis (LD25-45 ). Ablation of
caspase-1/11, but not apoptosis-associated speck-like
protein containing a CARD domain or
nucleotide-binding oligomerization domain-like receptor
protein 3 (NLRP3), improved neonatal survival following septic challenge compared with wild-type mice (P < 0·001), with decreased concentrations of inflammatory
cytokines in the serum and peritoneum. Surprisingly,
caspase-1/11(-/-) neonates also exhibited increased bone marrow and splenic haematopoietic stem cell expansion (P < 0·001), and increased concentrations of granulocyte and macrophage
colony-stimulating factors in the peritoneum (P < 0·001) after
sepsis. Ablation of
caspase-1/11 signalling was also associated with increased recruitment of peritoneal macrophages and neutrophils (P < 0·001), increased phagocytosis by neutrophils (P = 0·003), and decreased bacterial colonization (P = 0·02) in the peritoneum. These findings suggest that endogenous
caspase-1/11 activity, independent of the NLRP3
inflammasome, not only promotes the magnitude of the inflammatory response, but also suppresses protective immunity in the neonate, so contributing to innate immune dysfunction and poor survival in
neonatal sepsis.