CD16(+) Macrophages Mediate Fibrosis in Inflammatory Bowel Disease

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.