Irbesartan, an angiotensin II type 1 receptor blocker, inhibits colitis-associated tumourigenesis by blocking the MCP-1/CCR2 pathway

Kensuke Hachiya,Naoyuki Katayama,Masahiro Masuya,Kohshi Ohishi,Isao Tawara,Komei Nishimura,Junya Tsuboi,Keiki Nagaharu,Takuya Shiotani,Naoki Kuroda,Misao Yoneda

doi:10.1038/s41598-021-99412-8

Abstract

The introduction of anti-inflammatory therapies has enabled substantial improvement of disease activity in patients with inflammatory bowel diseases (IBD). However, IBD can lead to serious complications such as intestinal fibrosis and colorectal cancer. Therefore, novel therapies reducing the development of these complications are needed. Angiotensin II (Ang II) promotes tissue inflammation by stimulating the production of monocyte chemoattractant protein-1 (MCP-1) or proinflammatory cytokines. It plays a pivotal role in IBD progression. Although blockade of Ang II has been reported to ameliorate experimental colitis and reduce colorectal cancer risk, the cellular and molecular mechanisms remain poorly understood. Our previous work showed that irbesartan, an Ang II type 1 receptor blocker, reduced the number of C–C chemokine receptor 2-positive (CCR2+) monocytic cells in the inflamed pancreas. This study aimed to investigate the possible antifibrotic and antitumour effects of irbesartan using the azoxymethane/dextran sodium sulphate mouse model. Irbesartan suppressed MCP-1 production and the accumulation of Ly6C+CCR2+ monocytes and fibrocytes in the inflamed colon, downregulated the expression of type 1 collagen and matrix metalloproteinase 9 and inhibited the development of intestinal fibrosis and tumours. Our observations suggest that blocking the MCP-1/CCR2 pathway using irbesartan might be beneficial in preventing colitis-associated colon tumours.

Highlights

The prevalence of inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, is increasing worldwide
We investigated whether irbesartan, which potentially acts as a direct chemokine receptor 2 (CCR2) antagonist, prevents colitis, intestinal fibrosis and tumourigenesis, in an azoxymethane (AOM) and dextran sodium sulphate (DSS) mouse model of colitis-associated CRC29
We found that irbesartan suppressed the production of monocyte chemoattractant protein-1 (MCP-1), blocked the recruitment of Ly6ChighCCR2+ inflammatory monocytes to the inflamed colon through the MCP-1/CCR2 pathway and inhibited the development of colitis, fibrosis and tumours

Summary

Introduction

The prevalence of inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, is increasing worldwide. Ang II type 1 receptor (AT1R) blockers (ARBs), which are extensively used for the treatment of hypertension, are known to downregulate MCP-1 and proinflammatory cytokines and prevent chronic inflammation-associated remodelling in the liver, vessel, kidney and heart[24,25,26,27]. Irbesartan might have high affinity for CCR2 and might inhibit MCP-1 action beyond the blockade of AT1R It remains uncertain whether ARBs display a therapeutic efficacy in colitis, intestinal fibrosis and colitis-associated CRC. We found that irbesartan suppressed the production of MCP-1, blocked the recruitment of Ly6ChighCCR2+ inflammatory monocytes to the inflamed colon through the MCP-1/CCR2 pathway and inhibited the development of colitis, fibrosis and tumours. Irbesartan reversed the tumour progression even after colon tumours were established

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