D Ortiz-Masiá1, J Cosín-Roger2, S Calatayud2, C Hernández3, R Alós4, J Hinojosa4, J V Esplugues5, M D Barrachina6. 1. Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. 2. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. 3. FISABIO, Hospital Dr Peset, Valencia, Spain. 4. Hospital de Manises, Valencia, Spain. 5. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO, Hospital Dr Peset, Valencia, Spain. 6. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain dolores.barrachina@uv.es.
Abstract
BACKGROUND: The Notch signalling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease (CD) treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and hypoxia-inducible factors (HIFs). We analysed the role of HIFs in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration. METHODS: Human monocytes and U937-derived macrophages were polarized towards the M1 and M2 phenotypes and the expression levels of HIF-1α, HIF-2α, Jagged 1 (Jag1) and delta-like 4 (Dll4) were evaluated. The effects of macrophages on the expression of hairy and enhancer of split-1 (HES1, the main target of Notch signalling) and intestinal alkaline phosphatase (IAP, enterocyte marker) in epithelial cells in co-culture were also analysed. Phenotype macrophage markers and Notch signalling were evaluated in the mucosa of CD patients. RESULTS: M1 macrophages were associated with HIF-1-dependent induction of Jag1 and Dll4, which increased HES1 protein levels and IAP activity in co-cultured epithelial cells. In the mucosa of CD patients a high percentage of M1 macrophages expressed both HIF-1α and Jag1 while M2 macrophages mainly expressed HIF-2α and we detected a good correlation between the ratio of M1/M2 macrophages and both HES1 and IAP protein levels. CONCLUSION: M1, but not M2, macrophages are associated with HIF-1-dependent induction of Notch ligands and activation of epithelial Notch signalling pathway. In the mucosa of chronic CD patients, the prevalence of M2 macrophages is associated with diminution of Notch signalling and impaired enterocyte differentiation.
BACKGROUND: The Notch signalling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease (CD) treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and hypoxia-inducible factors (HIFs). We analysed the role of HIFs in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration. METHODS:Human monocytes and U937-derived macrophages were polarized towards the M1 and M2 phenotypes and the expression levels of HIF-1α, HIF-2α, Jagged 1 (Jag1) and delta-like 4 (Dll4) were evaluated. The effects of macrophages on the expression of hairy and enhancer of split-1 (HES1, the main target of Notch signalling) and intestinal alkaline phosphatase (IAP, enterocyte marker) in epithelial cells in co-culture were also analysed. Phenotype macrophage markers and Notch signalling were evaluated in the mucosa of CDpatients. RESULTS: M1 macrophages were associated with HIF-1-dependent induction of Jag1 and Dll4, which increased HES1 protein levels and IAP activity in co-cultured epithelial cells. In the mucosa of CDpatients a high percentage of M1 macrophages expressed both HIF-1α and Jag1 while M2 macrophages mainly expressed HIF-2α and we detected a good correlation between the ratio of M1/M2 macrophages and both HES1 and IAP protein levels. CONCLUSION: M1, but not M2, macrophages are associated with HIF-1-dependent induction of Notch ligands and activation of epithelial Notch signalling pathway. In the mucosa of chronic CDpatients, the prevalence of M2 macrophages is associated with diminution of Notch signalling and impaired enterocyte differentiation.
Authors: Norihiko Takeda; Ellen L O'Dea; Andrew Doedens; Jung-whan Kim; Alexander Weidemann; Christian Stockmann; Masataka Asagiri; M Celeste Simon; Alexander Hoffmann; Randall S Johnson Journal: Genes Dev Date: 2010-03-01 Impact factor: 11.361
Authors: Stephanie Dahan; Keren M Rabinowitz; Andrea P Martin; M Cecilia Berin; Jay C Unkeless; Lloyd Mayer Journal: Gastroenterology Date: 2010-11-04 Impact factor: 22.682
Authors: Koji Taniguchi; Li-Wha Wu; Sergei I Grivennikov; Petrus R de Jong; Ian Lian; Fa-Xing Yu; Kepeng Wang; Samuel B Ho; Brigid S Boland; John T Chang; William J Sandborn; Gary Hardiman; Eyal Raz; Yoshihiko Maehara; Akihiko Yoshimura; Jessica Zucman-Rossi; Kun-Liang Guan; Michael Karin Journal: Nature Date: 2015-02-25 Impact factor: 49.962
Authors: Haixia Xu; Jimmy Zhu; Sinead Smith; Julia Foldi; Baohong Zhao; Allen Y Chung; Hasina Outtz; Jan Kitajewski; Chao Shi; Silvio Weber; Paul Saftig; Yueming Li; Keiko Ozato; Carl P Blobel; Lionel B Ivashkiv; Xiaoyu Hu Journal: Nat Immunol Date: 2012-05-20 Impact factor: 25.606
Authors: K Radulovic; S Normand; A Rehman; A Delanoye-Crespin; J Chatagnon; M Delacre; N Waldschmitt; L F Poulin; J Iovanna; B Ryffel; P Rosenstiel; M Chamaillard Journal: Mucosal Immunol Date: 2017-11-15 Impact factor: 7.313
Authors: Ramon M Cabrera; Serena P H Mao; Chinmay R Surve; John S Condeelis; Jeffrey E Segall Journal: Breast Cancer Res Date: 2018-04-10 Impact factor: 6.466
Authors: Sudha B Singh; Cristina N Coffman; Amanda Carroll-Portillo; Matthew G Varga; Henry C Lin Journal: Front Cell Infect Microbiol Date: 2021-07-15 Impact factor: 5.293