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Complement C3a Receptor 1 and Complement C5a Receptor 1 Are Dual Contributors of Chronic-Plus-Binge-Induced Hepatic
Lauren N Rutt1, Shannon M Kirkpatrick1, Paige E Anton1
1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
The American Journal of Pathology
|May 30, 2026
Summary
Ethanol consumption affects liver macrophages by increasing intracellular complement components, contributing to persistent inflammation in alcohol-associated liver disease (ALD). Understanding this "complosome" offers new insights into ALD pathogenesis.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Alcohol-associated liver disease (ALD) is a major cause of liver mortality, characterized by chronic inflammation and immune dysfunction.
- The precise mechanisms underlying immune dysfunction in ALD remain incompletely understood.
Purpose of the Study:
- To investigate the role of the intracellular complement system, termed the "complosome", in the immune dysfunction observed in ALD.
- To characterize the expression and function of anaphylatoxin receptors (C3aR1 and C5aR1) on macrophages in the context of ethanol exposure.
Main Methods:
- Analysis of liver explants from ALD patients and healthy donors.
- Utilized chronic-plus-binge ethanol feeding in mice deficient in anaphylatoxin receptors.
- Employed in vitro models using bone marrow-derived macrophages (BMDMs) stimulated with ethanol and lipopolysaccharide (LPS).
Main Results:
- Anaphylatoxin receptor expression was elevated in macrophages from ALD patients.
- Ethanol increased C3aR1 and C5aR1 expression on Kupffer cells in mice, with C5aR1 deficiency protecting against liver injury.
- Ethanol and LPS increased intracellular complement components and anaphylatoxin receptors in BMDMs, impacting NLRP3 inflammasome activation and IL-1β production.
Conclusions:
- Ethanol exposure alters macrophage intracellular complement pathways, potentially driving non-resolving inflammation in ALD.
- Targeting intracellular complement components and anaphylatoxin receptors may offer therapeutic strategies for ALD.
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