# Receptor Cd74 integrates meta-inflammation in alcohol-associated liver disease

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $442,898

## Abstract

PROJECT SUMMARY
The role of inflammation in alcohol-associated liver disease has been thoroughly researched over the past few
decades. Despite this intensive focus on ALD pathophysiology, we have yet to realize meaningful
improvements to therapeutic design in humans. Our laboratory has established that macrophage migration
inhibitory factor (MIF) is a dynamic and multifaceted contributor to ALD. Furthermore, as our data will show,
specific depots of MIF, like hepatocytes and myeloid cells, contribute to ALD pathophysiology through distinct
mechanisms. The crosstalk between MIF and its cognate receptor, CD74, within the resident liver populations
and infiltrating cells from the periphery in ALD is not yet known. The overall goal for this proposal is to define
the contributions of MIF-CD74 signaling in ALD. Our preliminary data show that although hepatocyte- and
myeloid-derived Mif deficiency protected from ethanol-mediated steatosis, inflammation and cell death in the
liver, the hepatic transcriptomic program was divergent in these models despite equivalent protection from
injury. Interestingly, expression of Mif is robust in the hepatocyte compartment, but Cd74 is largely confined to
the monocytes/macrophages in a quiescent liver, but its expression is increased by ethanol, possibly due to
immune cell accumulation or upregulation of expression in hepatocytes. This suggests that the role of Cd74 in
ethanol feeding and ALD might be augmented throughout the progression of the disease and we will target
expression of Cd74 by multiple means in models of ethanol feeding. Moreover, the role of MIF in fibrosis
remains controversial, with several publications describing both protective and deleterious roles of MIF-CD74
signaling, but were limited to use of global knockouts. Our unique animal models and experience in ethanol
feeding will allow us to scrutinize the Mif-Cd74 pathway in multiple cellular depots in models of fibrosis. The
proposed research plan over the funding period will be divided into three specific aims that will 1) define and
characterize the role of Cd74 expression in hepatocytes and myeloid compartments during and after ethanol
feeding models in mice, 2) resolve the controversy of the role of MIF-CD74 pathway in hepatic fibrosis, and 3)
therapeutic targeting of hepatic MIF and CD74 via anti-sense oligonucleotide technology. These proposed
areas will have profound implications in innate immune responses in ALD, and will support scrutinizing the
distinctive, tissue-specific expression of mediators of tissue injury in chronic diseases of the liver.

## Key facts

- **NIH application ID:** 10981593
- **Project number:** 1R01AA031250-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Kyle Poulsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,898
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-01-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981593

## Citation

> US National Institutes of Health, RePORTER application 10981593, Receptor Cd74 integrates meta-inflammation in alcohol-associated liver disease (1R01AA031250-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10981593. Licensed CC0.

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