title: Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via αvβ1 integrin.
abstract: The intestinal immune system is constantly challenged by commensal bacteria; therefore, it must maintain quiescence via several regulatory mechanisms. Although intestinal macrophages (Ms) have been implicated in repression of excessive inflammation, it remains unclear how their functions are regulated during inflammation. In this study, we report that semaphorin 7A (Sema7A), a GPI-anchored semaphorin expressed in intestinal epithelial cells (IECs), induces IL-10 production by intestinal Mϕs to regulate intestinal inflammation. Sema7A-deficient mice showed severe signs of dextran sodium sulfate-induced colitis due to reduced intestinal IL-10 levels. We further identified CX3CR1(+)MHC class II(int)F4/80(hi)CD11b(hi) Mϕs as the main producers of IL-10 via αvβ1 integrin in response to Sema7A. Notably, Sema7A was predominantly expressed on the basolateral side of IECs, and its expression pattern was responsible for protective effects against dextran sodium sulfate-induced colitis and IL-10 production by Mϕs during interactions between IECs and Mϕs. Furthermore, we determined that the administration of recombinant Sema7A proteins ameliorated the severity of colitis, and these effects were diminished by IL-10-blocking Abs. Therefore, our findings not only indicate that Sema7A plays crucial roles in suppressing intestinal inflammation through αvβ1 integrin, but also provide a novel mode of IL-10 induction via interactions between IECs and Mϕs.
authors.affiliation: Department of Immunopathology, World Premier International Research Center, Osaka University, Suita City, Osaka 565-0871, Japan.
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.forename: Noriko
authors.initials: N
authors.lastname: Takegahara
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Saori
authors.initials: S
authors.lastname: Ohmae
authors.forename: Dong-Ju
authors.initials: DJ
authors.lastname: You
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002450:Cell Communication; D003092:Colitis / Q000209:etiology / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007422:Intestines; D008264:Macrophages; D051379:Mice; D019030:Receptors, Vitronectin / Q000502:physiology*; D039961:Semaphorins / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D019030:Receptors, Vitronectin; C485571:Sema7a protein, mouse; D039961:Semaphorins; C094340:integrin alphavbeta1; D016753:Interleukin-10