Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance

Junya Itakura, Miwa Sato, Toshihiro Ito, Megumi Mino, Soichiro Fushimi, Sakuma Takahashi, Teizo Yoshimura, Akihiro Matsukawa

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number12833
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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Peritonitis
Inflammation
Punctures
Ligation
MAP Kinase Signaling System
Sepsis
Complement 3d Receptors
Macrophages
Complement C1
Leukocytes
Bacterial Load
Chemokines
Protein Deficiency
Mitogen-Activated Protein Kinase Kinases
Innate Immunity
Critical Illness
Lipopolysaccharides
Protein Domains
Cause of Death
Neutrophils

ASJC Scopus subject areas

  • General

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Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance. / Itakura, Junya; Sato, Miwa; Ito, Toshihiro; Mino, Megumi; Fushimi, Soichiro; Takahashi, Sakuma; Yoshimura, Teizo; Matsukawa, Akihiro.

In: Scientific Reports, Vol. 7, No. 1, 12833, 01.12.2017.

Research output: Contribution to journalArticle

Itakura, Junya ; Sato, Miwa ; Ito, Toshihiro ; Mino, Megumi ; Fushimi, Soichiro ; Takahashi, Sakuma ; Yoshimura, Teizo ; Matsukawa, Akihiro. / Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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