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

BACKGROUND & AIM: Alcohol consumption, through increasing intestinal permeability and causing hepatocytes damage, leads to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs). These molecules stimulate hepatic macrophages (MΦs) and activate NF-κB, resulting in inflammation and exacerbating alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in the majority of the heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells and 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 MΦ activation were compared among WT, IL-33(-/-) and ST2(-/-) mice in several models.

RESULTS: Elevations of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant amount of 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 MΦs. In contrast, when extracellular IL-33 was markedly elevated, both IL-33(-/-) and ST2(-/-) mice developed attenuated liver injury and inflammation compared with WT 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 MΦs, 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 MΦs, thereby protecting against alcohol-induced liver damage, whereas in 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 MΦs.