IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages

Meng Wang; Guannan Shen; Liangguo Xu; Xiaodong Liu; Jared M Brown; Dechun Feng; Ruth Ann Ross; Bin Gao; Suthat Liangpunsakul; Cynthia Ju

doi:10.1016/j.jhep.2017.08.023

IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages

J Hepatol. 2017 Sep 21:S0168-8278(17)32263-8. doi: 10.1016/j.jhep.2017.08.023. Online ahead of print.

Authors

Meng Wang¹, Guannan Shen¹, Liangguo Xu², Xiaodong Liu³, Jared M Brown¹, Dechun Feng⁴, Ruth Ann Ross⁵, Bin Gao⁴, Suthat Liangpunsakul⁶, Cynthia Ju⁷

Affiliations

¹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, USA.
² School of Life Science, Jiangxi Normal University, China.
³ Department of Pharmacy, Shengjing Hospital, China Medical University, China.
⁴ Laboratory of Liver Diseases, NIAAA, NIH, USA.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
⁷ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, USA. Electronic address: Cynthia.ju@ucdenver.edu.

PMID: 28870670
DOI: 10.1016/j.jhep.2017.08.023

Abstract

Background & aim: Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-κB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-κB activation. The role of IL-33/ST2 in ALD has not been studied.

Methods: Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild-type, IL-33^-/- and ST2^-/- mice in several models.

Results: Elevation of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2-deletion exacerbated ALD, through enhancing NF-κB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33^-/- and ST2^-/- mice compared to wild-type mice.

Conclusion: Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-κB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL-33/ST2 signaling and exacerbates tissue damage.

Lay summary: In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages.

Keywords: IL-33; Inflammation; Liver macrophages; NF-κB; ST2.