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Updated: Feb 21, 2026
Colon Ascendens Stent Peritonitis CASP - a Standardized Model for Polymicrobial Abdominal Sepsis
Published on: December 18, 2010
Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial
Junya Itakura1, Miwa Sato1, Toshihiro Ito1,2
1Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan.
Abstract:
Sepsis is an infection-induced systemic inflammatory syndrome and a major cause of death for critically ill patients. Here, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences host defense against polymicrobial sepsis (PMS) induced by cecal ligation and puncture (CLP). Compared to wild-type mice, Spred2-/- mice exhibited higher survival rates with increased level of leukocyte infiltration and local chemokine production and reduced plasma and peritoneal bacterial loads after CLP. The MEK inhibitor U0126 significantly reduced LPS-induced chemokine production by Spred2-/- resident macrophages in vitro, and decreased CLP-induced leukocyte infiltration in vivo. Spred2-/- resident macrophages, but not neutrophils or elicited macrophages, exhibited increased phagocytic activity. Interestingly, surface expression of complement receptor 1/2 (CR1/2) was increased in Spred2-/- resident macrophages in response to lipopolysaccharide in a manner dependent on the ERK/MAPK pathway, and blocking CR1/2 in vivo resulted in reduced leukocyte infiltration and increased bacterial loads after CLP. Taken together, our results indicate that Spred2-deficiency protects mice from PMS via increased activation of the ERK/MAPK pathway and subsequent increase in innate immune responses. Thus, inhibiting Spred2 may present a novel means to prevent the development of PMS.
Insights
Spred2 deficiency enhances host defense against polymicrobial sepsis (PMS) by boosting innate immune cell activity and reducing bacterial load. This suggests inhibiting Spred2 could be a novel therapeutic strategy for sepsis treatment.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Sepsis is a life-threatening condition caused by dysregulated host response to infection.
- Sprouty-related EVH1-domain-containing protein 2 (Spred2) negatively regulates the Ras/Raf/ERK/MAPK pathway.
- The role of Spred2 in sepsis pathogenesis remains unclear.
Purpose of the Study:
- To investigate the impact of Spred2 deficiency on host defense during polymicrobial sepsis (PMS).
- To elucidate the underlying molecular mechanisms, particularly the involvement of the ERK/MAPK pathway.
Main Methods:
- Polymicrobial sepsis was induced using cecal ligation and puncture (CLP) in Spred2 knockout (Spred2-/-) and wild-type mice.
- Leukocyte infiltration, chemokine production, bacterial load, and macrophage phagocytic activity were assessed.
- The MEK inhibitor U0126 and complement receptor 1/2 (CR1/2) blocking were used to explore pathway involvement.
Main Results:
- Spred2-/- mice showed significantly higher survival rates after CLP compared to wild-type controls.
- Leukocyte infiltration, local chemokine production, and phagocytic activity of resident macrophages were increased in Spred2-/- mice.
- Enhanced ERK/MAPK pathway activation and increased CR1/2 expression on macrophages were observed in Spred2-/- mice, contributing to improved bacterial clearance.
Conclusions:
- Spred2 deficiency confers protection against polymicrobial sepsis by enhancing innate immune responses through the ERK/MAPK pathway.
- Targeting Spred2 may represent a promising therapeutic approach for managing sepsis.
