# The role of Kupffer cells in alcohol-induced liver disease

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $376,136

## Abstract

SUMMARY
 Alcohol-induced liver disease is a significant clinical problem. Kupffer cells (liver resident
macrophages) play crucial roles in the inflammatory responses of alcoholic liver disease. Macrophages
have distinct functional states with pro-inflammatory M1 type and anti-inflammatory M2 type. The
mechanisms that govern this classical polarization remain to be elucidated. The goals of this study are
to: 1) Identify a novel molecular switch that determines M1 vs. M2 polarization in the context of ethanol-
induced hepatic steatosis and injury and 2) Evaluate the potential of Kupffer cells as a therapeutic
target.
 An endoplasmic reticulum (ER) resident protein, Nogo-B, also known as reticulon 4B, has been
implicated in maintaining ER structure. In the liver, Nogo-B is restricted to non-parenchymal cells
including Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells, but not in
hepatocytes. Our preliminary data demonstrate that Nogo-B levels correlate with the severity of
alcoholic liver disease in patients. Nogo-B levels in Kupffer cells were positively associated with M1
polarization and negatively with M2 polarization in human liver specimens. In mice, the absence of
Nogo-B resulted in significantly lower levels of hepatic steatosis and injury than wildtype (WT) mice in
response to an ethanol diet. Kupffer cells from Nogo-B knockout (KO) mice showed significantly
decreased expression of M1 markers, including inducible nitric oxide synthase (iNOS), interleukin 1β
(IL1β) and tumor necrosis factor α (TNFα), but exhibited significantly increased M2 markers, such as
CD163 and arginase-1, compared to their WT counterparts. Importantly, iNOS, IL1β and TNFα have
been reported to enhance hepatic steatosis in alcoholic or non-alcoholic settings and are induced by
nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB). Nogo-B KO Kupffer cells
exhibited significantly increased ER stress, a factor that induces M2 polarization. Based on these
observations from human specimens and animal studies, we hypothesize that Nogo-B regulates
Kupffer cell polarization and facilitates hepatic steatosis/injury in response to chronic ethanol
consumption and that selective deletion of Nogo-B in Kupffer cells will reduce ethanol-induced hepatic
injury. To test these hypotheses, we propose the following three aims: 1) Determine the mechanism by
which Nogo-B facilitates M1 polarization of Kupffer cells in response to chronic ethanol consumption, 2)
Determine the mechanism by which lack of Nogo-B facilitates M2 polarization of Kupffer cells in
response to chronic ethanol consumption, and 3) Determine whether deletion of Nogo-B in Kupffer cells
reduces hepatic steatosis and injury in ethanol-fed mice.

## Key facts

- **NIH application ID:** 9987412
- **Project number:** 5R01AA025342-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YASUKO IWAKIRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,136
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987412

## Citation

> US National Institutes of Health, RePORTER application 9987412, The role of Kupffer cells in alcohol-induced liver disease (5R01AA025342-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987412. Licensed CC0.

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