Aberrant Inflammation and Lethality to Septic Peritonitis in Mice Lacking STAT3 in Macrophages and Neutrophils

Akihiro Matsukawa, Kiyoshi Takeda, Shinji Kudo, Takako Maeda, Motoko Kagayama, Shizuo Akira

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

Abstract

Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. In the present study, we demonstrate a pivotal role of Stat3 expressed in innate immune cells during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis induced by CLP. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. Despite enhanced inflammatory responses, the mice failed to facilitate bacterial clearance as compared with the control mice. In addition, the mice exhibited an increased lethality after i.p. inoculation of live bacteria recovered from CLP-mice. In vitro, resident peritoneal macrophages from mice with Stat3 deficiency impaired bactericidal activity relative to the control whereas productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2 and LPS. Elicited macrophages and neutrophils with Stat3 deficiency also impaired bactericidal activity as compared with those with Stat3. Lysosomal enzyme release, an effector molecule for bacterial clearance, was significantly decreased in elicited leukocytes with Stat3 deficiency while increasing the production of inflammatory cytokines. Altogether, these results suggest that macrophage/neutrophil-specific STAT3 is crucial in not only modulating multiple organ failure associated with systemic inflammation but also intensifying the bactericidal activity, which highlight the significance of cell-specific Stat3 in the protective immunity during sepsis.

Original languageEnglish
Pages (from-to)6198-6205
Number of pages8
JournalJournal of Immunology
Volume171
Issue number11
DOIs
Publication statusPublished - Dec 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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