CD16+ Macrophages Mediate Fibrosis in Inflammatory Bowel Disease

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


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.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cell Count
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / complications*
  • Colitis / metabolism
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / pathology*
  • Crohn Disease / pathology*
  • Female
  • Fibrosis / etiology
  • Fibrosis / genetics*
  • Humans
  • Interleukin-4 / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology*
  • Lectins, C-Type / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Mannose Receptor
  • Mannose-Binding Lectins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Cell Surface / metabolism
  • Receptors, IgG
  • STAT6 Transcription Factor / genetics*
  • Trinitrobenzenesulfonic Acid
  • Wnt Proteins / metabolism
  • Young Adult


  • Fcgr3 protein, mouse
  • Lectins, C-Type
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, IgG
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Wnt Proteins
  • Wnt6 protein, mouse
  • Interleukin-4
  • Trinitrobenzenesulfonic Acid