Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model

Authors

Hami Hemati, University of KentuckyFollow
Madison B. Blanton, University of Kentucky
Heather E. True, University of KentuckyFollow
Jude Koura, University of Kentucky
Rupak Khadka, Oregon National Primate Research Center
Kathleen A. Grant, Oregon National Primate Research Center
Ilhem Messaoudi, University of KentuckyFollow

Abstract

Alcohol-induced dysregulation of microglial activity is associated with neuroinflammation, cognitive decline, heightened risk for neurodegenerative diseases, alcohol dependence, and escalation of alcohol drinking. Given the challenge of longitudinally sampling primary microglia, we optimized an in vitro method to differentiate peripheral blood mononuclear cells (PBMC) from rhesus macaque (RM) into induced microglia-like cells (RM-iMGLs). The RM-iMGLs displayed transcriptional profiles distinct from monocyte progenitors and closely resembling primary microglia. Notably, morphological features showed that differentiated RM-iMGLs derived from subjects with chronic alcohol consumption (CAC), while bigger, exhibited a bipolar-like morphology. Additionally, dysregulation in key inflammatory and regulatory markers, along with increased baseline phagocytic activity, was observed in CAC-derived RM-iMGLs. Phenotypic and functional assessments following LPS stimulation indicated the enrichment of a CD86+ hyper-inflammatory subpopulation in RM-iMGLs derived from ethanol-consuming animals, accompanied by an overall increase in immune reactivity, indicative of a heightened inflammatory state. Collectively, these findings demonstrate that in vitro differentiation of PBMCs offers a minimally invasive yet highly translational approach to studying the impact of CAC on microglial function and that CAC reshapes both functional and transcriptional profiles of RM-iMGLs, which require further investigation at the single-cell level.

Document Type

Article

Publication Date

2025

Notes/Citation Information

0889-1591/© 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bbi.2025.07.022

Funding Information

We thank members of the Messaoudi laboratory for their help and feedback. We thank Dr. Delphine Malherbe for reading the manuscript and providing feedback. This work was supported by R01AA028735-04, U01AA013510-20, R24AA019431-14, P51OD011092, and F31AA031600-01A1.

Repository Citation

Hemati, Hami; Blanton, Madison B.; True, Heather E.; Koura, Jude; Khadka, Rupak; Grant, Kathleen A.; and Messaoudi, Ilhem, "Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model" (2025). Microbiology, Immunology, and Molecular Genetics Faculty Publications. 201.
https://uknowledge.uky.edu/microbio_facpub/201