CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis

Makoto Ishii, Koichiro Asano, Ho Namkoong, Sadatomo Tasaka, Kosuke Mizoguchi, Takahiro Asami, Hirofumi Kamata, Yoshifumi Kimizuka, Hiroshi Fujiwara, Yohei Funatsu, Shizuko Kagawa, Jun Miyata, Ken Ishii, Masataka Nakamura, Hiroyuki Hirai, Kinya Nagata, Steven L. Kunkel, Naoki Hasegawa, Tomoko Betsuyaku

Research output: Contribution to journalArticle

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Abstract

Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD2 and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2 -/-) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2 -/- mice, blunting CLP-induced lethality in CRTH2 -/- mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH22/2 mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2 -/- mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis. Copyright

Original languageEnglish
Pages (from-to)5655-5664
Number of pages10
JournalJournal of Immunology
Volume188
Issue number11
DOIs
Publication statusPublished - 2012 Jun 1

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Sepsis
Neutrophils
Punctures
Ligation
Formyl Peptide Receptor
Prostaglandin D2
Th2 Cells
Neutrophil Infiltration
Bacterial Load
Peritoneum
Acetylation
Arachidonic Acid
Epigenomics
Knockout Mice
Interleukin-10
Histones
Interleukin-6
Anti-Inflammatory Agents
Pharmacology
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Ishii, M., Asano, K., Namkoong, H., Tasaka, S., Mizoguchi, K., Asami, T., ... Betsuyaku, T. (2012). CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. Journal of Immunology, 188(11), 5655-5664. https://doi.org/10.4049/jimmunol.1102330

CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. / Ishii, Makoto; Asano, Koichiro; Namkoong, Ho; Tasaka, Sadatomo; Mizoguchi, Kosuke; Asami, Takahiro; Kamata, Hirofumi; Kimizuka, Yoshifumi; Fujiwara, Hiroshi; Funatsu, Yohei; Kagawa, Shizuko; Miyata, Jun; Ishii, Ken; Nakamura, Masataka; Hirai, Hiroyuki; Nagata, Kinya; Kunkel, Steven L.; Hasegawa, Naoki; Betsuyaku, Tomoko.

In: Journal of Immunology, Vol. 188, No. 11, 01.06.2012, p. 5655-5664.

Research output: Contribution to journalArticle

Ishii, M, Asano, K, Namkoong, H, Tasaka, S, Mizoguchi, K, Asami, T, Kamata, H, Kimizuka, Y, Fujiwara, H, Funatsu, Y, Kagawa, S, Miyata, J, Ishii, K, Nakamura, M, Hirai, H, Nagata, K, Kunkel, SL, Hasegawa, N & Betsuyaku, T 2012, 'CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis', Journal of Immunology, vol. 188, no. 11, pp. 5655-5664. https://doi.org/10.4049/jimmunol.1102330
Ishii, Makoto ; Asano, Koichiro ; Namkoong, Ho ; Tasaka, Sadatomo ; Mizoguchi, Kosuke ; Asami, Takahiro ; Kamata, Hirofumi ; Kimizuka, Yoshifumi ; Fujiwara, Hiroshi ; Funatsu, Yohei ; Kagawa, Shizuko ; Miyata, Jun ; Ishii, Ken ; Nakamura, Masataka ; Hirai, Hiroyuki ; Nagata, Kinya ; Kunkel, Steven L. ; Hasegawa, Naoki ; Betsuyaku, Tomoko. / CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. In: Journal of Immunology. 2012 ; Vol. 188, No. 11. pp. 5655-5664.
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AU - Asano, Koichiro

AU - Namkoong, Ho

AU - Tasaka, Sadatomo

AU - Mizoguchi, Kosuke

AU - Asami, Takahiro

AU - Kamata, Hirofumi

AU - Kimizuka, Yoshifumi

AU - Fujiwara, Hiroshi

AU - Funatsu, Yohei

AU - Kagawa, Shizuko

AU - Miyata, Jun

AU - Ishii, Ken

AU - Nakamura, Masataka

AU - Hirai, Hiroyuki

AU - Nagata, Kinya

AU - Kunkel, Steven L.

AU - Hasegawa, Naoki

AU - Betsuyaku, Tomoko

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N2 - Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD2 and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2 -/-) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2 -/- mice, blunting CLP-induced lethality in CRTH2 -/- mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH22/2 mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2 -/- mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis. Copyright

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