title: CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis.
abstract: Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD(2) 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 CRTH2(-/-) 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.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. ishii@z6.keio.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.forename: Ho
authors.initials: H
authors.lastname: Namkoong
authors.forename: Sadatomo
authors.initials: S
authors.lastname: Tasaka
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizoguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Asami
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kamata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kimizuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Yohei
authors.initials: Y
authors.lastname: Funatsu
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kagawa
authors.forename: Jun
authors.initials: J
authors.lastname: Miyata
authors.forename: Ken
authors.initials: K
authors.lastname: Ishii
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Kinya
authors.initials: K
authors.lastname: Nagata
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000276:immunology; D002432:Cecum / Q000601:surgery; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D005260:Female; D018836:Inflammation Mediators / Q000502:physiology; D008026:Ligation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D011677:Punctures; D011971:Receptors, Immunologic / Q000172:deficiency / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000502:physiology*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor