Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease

Dong Hyuk Seo,Won Ho Kim,Tae Il Kim,Da Hye Kim,Jae Hyeon Kim,Xiumei Che,Jae Hee Cheon,Min Seob Kwak,Soochan Kim,Hyun Woo Ma,Seung Won Kim

doi:10.1038/s41598-017-00840-2

Abstract

Interleukin 33 (IL-33) that signals through the ST2 receptor has emerged as a critical modulator in several inflammatory disorders, including inflammatory bowel disease (IBD). However, the precise mechanisms by which IL-33 modulates IBD are controversial. The aim of this study was thus to clarify the role of IL-33 in IBD. The plasma levels of IL-33 were significantly decreased, but soluble ST2 levels were increased in patients with IBD compared to healthy individuals. Moreover, IL-33 restored goblet cell numbers and induced macrophage switching from the M1 to the M2 phenotype. These effects were sufficient to ameliorate colitis in dextran sodium sulfate, trinitrobenzene sulfonic acid, and peritoneal cavity cell transfer models. IL-33 facilitated goblet cell restoration via modulating macrophages toward the M2 phenotype. In addition, wound healing was significantly faster in IL-33-treated human monocyte-derived macrophages than in control cells, which could be attributed to increased polarisation into M2 macrophages. We found that patients with IBD show decreased serum levels of IL-33 compared with healthy individuals and that IL-33 can attenuate colitis and aid tissue repair in mice. The mechanism by which IL-33 exerts these effects appears to involve the stimulation of differentiation of goblet cells and M2 macrophages.

Highlights

Inflammatory bowel diseases (IBDs) are chronic relapsing disorders of the intestine that are caused by complex interactions of environmental and genetic factors, along with subsequent changes in immune dysregulation
As shown in Fig. 1a−d, we found that the serum Interleukin 33 (IL-33) levels in patients with IBD were lower than those in normal controls (P < 0.012: normal controls, 0.513 ± 0.665 ng/ml; IBD, 0.242 ± 0.436 ng/ml; Crohn’s disease (CD), 0.381 ± 0.582 ng/ml; ulcerative colitis (UC), 0.185 ± 0.394 ng/ml; intestinal Behçet’s disease (BD), 0.160 ± 0.229 ng/ml), whereas the soluble receptor ST2 (sST2) levels in patients with IBD were higher than those in normal controls (P < 0.001: normal controls, 4.246 ± 0.737 ng/ ml; IBD, 5.344 ± 1.162 ng/ml; CD, 5.110 ± 1.054 ng/ml; UC, 5.581 ± 1.169 ng/ml; BD, 5.214 ± 1.174 ng/ml)
IL-33 is synthesised as a precursor and can be cleaved by caspase-1 and -3, the cleavage products are biologically less active than their precursor[40]

Summary

Introduction

Inflammatory bowel diseases (IBDs) are chronic relapsing disorders of the intestine that are caused by complex interactions of environmental and genetic factors, along with subsequent changes in immune dysregulation. It was reported that IL-33 colocalised with F4/80+ myeloid-derived cells in the inflamed intestinal lamina propria of mice in an oxazolone colitis model[10] Given this finding, we speculated that IL-33 can directly modulate intestinal immune responses by driving the M1-to-M2 macrophage switch and macrophage-goblet cell cross-talk. The aim of our study was to investigate the associations between IL-33 and IBD by exploring whether IL-33 contributes to the resolution of colitis and tissue repair by functional phenotype modulation of goblet cells and macrophages. To this end, we assessed the effect of IL-33 on colitis using well-established acute murine models of colitis.

Objectives

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Conclusion