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J Crohns Colitis. 2018 Apr 27;12(5):589-599. doi: 10.1093/ecco-jcc/jjx185.

CD16+ Macrophages Mediate Fibrosis in Inflammatory Bowel Disease.

Author information

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.

PMID:
29304229
DOI:
10.1093/ecco-jcc/jjx185
[Indexed for MEDLINE]

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