Anti-High Mobility Group Box 1 Neutralizing-Antibody Ameliorates Dextran Sodium Sulfate Colitis in Mice.

Liping Chen,De’An Tian,Meiping Yu,Jian Han,Lu Wang,Junhua Li,Fang Xiao,Ursula Seidler,Binghua Sun,Ying Wang,Qi Zhou,Zhenghao Ye,Yu Chen

doi:10.3389/fimmu.2020.585094

Abstract

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein in mammals. When released into the extracellular space, it acts as a damage-associated molecular pattern. This study investigates whether increased HMGB1 levels are found in the intestinal mucosa of ulcerative colitis (UC) patients, and whether an anti-HMGB1 neutralizing-antibody (HnAb) can inhibit the intestinal inflammation elicited by dextran sulfate sodium (DSS) in mice. Because toll-like receptor 4 (TLR4) is implicated in HMGB1-mediated immune cell activation, DSS colitis was also elicited in TLR4-deficient mice in the presence and absence of HnAb. The expression of HMGB1 in UC patients was examined. HnAb was administered via intraperitoneal injection to TLR4 deficient mice and their wild-type littermates, both being induced to colitis with DSS. Finally, the protective effect of HnAb and TLR4 deficiency were evaluated. In UC patients, HMGB1 was up-regulated in the inflamed colon. When administered during DSS application, HnAb alleviated the severity of colitis with a lower disease activity index, limited histological damages, and reduced production of proinflammatory cytokines. This antibody also limited colonic barrier loss, decreased colonic lamina propria macrophages and partially reversed the DSS treatment-associated dysbiosis. The protective effect of this antibody was enhanced in TLR4-deficient mice in some aspects, indicating that both additional HMGB1-mediated as well as TLR4-mediated inflammatory signaling pathways were involved in the induction of colitis by DSS. HnAb ameliorated colitis via macrophages inhibition and colonic barrier protection. It may therefore be a novel treatment option in colitis.

Highlights

Inflammatory bowel diseases (IBD) represents a group of chronic relapsing inflammatory disorder, including Crohn’s disease and ulcerative colitis (UC)
Expression of High mobility group box 1 (HMGB1) was elevated in serum, intestinal tissues or feces of patients and mouse models of IBD [6, 7], and HMGB1 was transported from nucleus to the cytoplasm during colonic inflammation [8, 9]
The messenger RNA (mRNA) expression of tumor necrosis factor-a (TNF-a), interferon g (IFN-g), IL-1b, IL-6, and IL-8 was significantly increased in the inflamed tissues compared to adjacent non-inflamed tissues, which was consistent with the endoscopic manifestations

Summary

Introduction

Inflammatory bowel diseases (IBD) represents a group of chronic relapsing inflammatory disorder, including Crohn’s disease and ulcerative colitis (UC). While initially highly efficient in many patients, the efficacy of biologics in inducing and maintaining clinical remission of IBD over extended period of times remains below 50% of treated patients [2, 3]. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein in mammalian tissues, and is responsible for maintaining the structure of nucleosomes and regulating gene transcription [4]. HMGB1 has been identified as a pro-inflammatory cytokine or damage-associated molecular pattern implicated in several inflammatory disorders, such as septic shock, rheumatoid arthritis, systemic lupus erythematosus, and recently in IBD [5]. HMGB1 was found to aggravate colonic inflammation by activating the immune response in colitis [11]

Objectives

Methods

Results

Conclusion