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Updated: Apr 17, 2026
A Controlled Mouse Model for Neonatal Polymicrobial Sepsis
Published on: January 27, 2019
Improved emergency myelopoiesis and survival in neonatal sepsis by caspase-1/11 ablation
Lori F Gentile1, Angela L Cuenca, Alex G Cuenca
1Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
Insights
Neonatal sepsis survival improves when caspase-1/11 is blocked, independent of NLRP3 inflammasome. This enhances immune cell function and reduces bacterial load, suggesting a new therapeutic target for infant sepsis.
Area of Science:
- Immunology
- Neonatal Sepsis
- Inflammasome Biology
Background:
- Neonatal sepsis causes over a million deaths annually, particularly in premature infants.
- The inflammasome, via caspase-1, regulates IL-1β and IL-18, crucial for innate immunity.
- Caspase-1 activity in endotoxic shock suggests a role in excessive inflammation and mortality.
Purpose of the Study:
- To investigate the role of caspase-1 and the inflammasome in neonatal inflammation, immunity, and myelopoiesis during polymicrobial sepsis.
- To determine if caspase-1/11 signaling impacts survival, inflammatory responses, and host defense in neonatal sepsis.
Main Methods:
- Utilized a low-lethality caecal slurry model of intra-abdominal sepsis in neonatal (5-7 days) wild-type and caspase-1/11(-/-) mice.
- Assessed survival rates, serum and peritoneal inflammatory cytokine concentrations, bone marrow and splenic hematopoietic stem cell expansion, and peritoneal immune cell recruitment and function.
Main Results:
- Ablation of caspase-1/11 significantly improved neonatal survival (P < 0.001) with reduced inflammatory cytokines.
- Caspase-1/11 deficiency led to increased hematopoietic stem cell expansion and granulocyte-macrophage colony-stimulating factors.
- Absence of caspase-1/11 enhanced neutrophil and macrophage recruitment, phagocytosis, and decreased bacterial colonization.
Conclusions:
- Endogenous caspase-1/11 activity, independent of the NLRP3 inflammasome, exacerbates neonatal sepsis inflammation and impairs protective immunity.
- Blocking caspase-1/11 signaling improves neonatal survival by enhancing immune cell function and reducing bacterial burden.
- Caspase-1/11 represents a potential therapeutic target for improving outcomes in neonatal sepsis.
Abstract:
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.
