Pedro Salvador1, Dulce Carolina Macías-Ceja2, Laura Gisbert-Ferrándiz1, Carlos Hernández2, David Bernardo3, Rafael Alós4, Francisco Navarro-Vicente5, Juan Vicente Esplugues1, Dolores Ortiz-Masiá6, Maria Dolores Barrachina1, Sara Calatayud1. 1. Departamento de Farmacología and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Facultad de Medicina, Universidad de Valencia, Valencia, Spain. 2. FISABIO, Hospital Dr Peset, Valencia, Spain. 3. Unidad de Gastroenterología, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. 4. Servicio de Cirugía, Hospital de Sagunto, Sagunto, Valencia, Spain. 5. Servicio de Cirugía, Hospital de Manises, Manises, Valencia, Spain. 6. Departamento de Medicina and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Abstract
BACKGROUND AND AIMS: Fibrosis is a common complication of Crohn's disease [CD], and is related to dysregulated tissular repair following inflammation, in which macrophages play a central role. We have previously observed that STAT6-/- mice present delayed mucosal recovery after 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis due to a deficiency in reparatory interleukin-4 [IL4]/STAT6-dependent M2 macrophages, which can be reverted by the exogenous transfer of this cell type. In the present study, we analyse the role of STAT6-dependent macrophages in intestinal fibrosis. METHODS: Colitis was induced by weekly intra-rectal administration of TNBS [6 weeks] to STAT6-/- mice and wild-type [WT] animals. Colonic surgical resections were obtained from CD patients and from colon cancer patients. RESULTS: Chronic colitis provoked a fibrogenic response in STAT6-/- mice, but not in WT animals. An accumulation of M2 macrophages, defined as CD206+ cells, was observed in WT mice, but not in STAT6-/- animals. Instead, the latter group showed an increase in CD16+ macrophages that correlated with the expression of fibrogenic markers. CD16+ macrophages were also increased in the damaged mucosa of Crohn's disease patients with stenotic or penetrating complications. Finally, administration of IL4-treated WT macrophages to STAT6-/- mice reduced TNBS-induced fibrosis. CONCLUSIONS: Our study demonstrates that STAT6 deficiency dysregulates the macrophage response to inflammatory outbursts by increasing the presence of a population of CD16+ macrophages that seems to contribute to intestinal fibrosis.
BACKGROUND AND AIMS: Fibrosis is a common complication of Crohn's disease [CD], and is related to dysregulated tissular repair following inflammation, in which macrophages play a central role. We have previously observed that STAT6-/- mice present delayed mucosal recovery after 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis due to a deficiency in reparatory interleukin-4 [IL4]/STAT6-dependent M2 macrophages, which can be reverted by the exogenous transfer of this cell type. In the present study, we analyse the role of STAT6-dependent macrophages in intestinal fibrosis. METHODS: Colitis was induced by weekly intra-rectal administration of TNBS [6 weeks] to STAT6-/- mice and wild-type [WT] animals. Colonic surgical resections were obtained from CD patients and from colon cancer patients. RESULTS: Chronic colitis provoked a fibrogenic response in STAT6-/- mice, but not in WT animals. An accumulation of M2 macrophages, defined as CD206+ cells, was observed in WT mice, but not in STAT6-/- animals. Instead, the latter group showed an increase in CD16+ macrophages that correlated with the expression of fibrogenic markers. CD16+ macrophages were also increased in the damaged mucosa of Crohn's disease patients with stenotic or penetrating complications. Finally, administration of IL4-treated WT macrophages to STAT6-/- mice reduced TNBS-induced fibrosis. CONCLUSIONS: Our study demonstrates that STAT6 deficiency dysregulates the macrophage response to inflammatory outbursts by increasing the presence of a population of CD16+ macrophages that seems to contribute to intestinal fibrosis.
Authors: Dulce C Macias-Ceja; Sandra Coll; Cristina Bauset; Marta Seco-Cervera; Laura Gisbert-Ferrándiz; Francisco Navarro; Jesus Cosin-Roger; Sara Calatayud; María D Barrachina; Dolores Ortiz-Masia Journal: Biomedicines Date: 2022-05-08
Authors: B Sensi; L Siragusa; C Efrati; L Petagna; M Franceschilli; V Bellato; A Antonelli; C Arcudi; M Campanelli; S Ingallinella; A M Guida; A Divizia Journal: J Immunol Res Date: 2020-12-26 Impact factor: 4.818
Authors: Jesus Cosin-Roger; Francisco Canet; Dulce C Macias-Ceja; Laura Gisbert-Ferrándiz; Dolores Ortiz-Masiá; Juan V Esplugues; Rafael Alós; Francisco Navarro; María D Barrachina; Sara Calatayud Journal: Cells Date: 2019-09-13 Impact factor: 6.600
Authors: Nicholas S Rhoades; Sara M Hendrickson; Kamm Prongay; Andrew Haertel; Leanne Gill; Robert A Edwards; Laura Garzel; Mark K Slifka; Ilhem Messaoudi Journal: Mucosal Immunol Date: 2021-06-22 Impact factor: 7.313