Related Experiment Video
Updated: May 4, 2026
An In vitro Model to Study Heterogeneity of Human Macrophage Differentiation and Polarization
Published on: June 12, 2013
Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular
Anna Podleśny-Drabiniok1, Carmen Romero-Molina1, Tulsi Patel1
1Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Abstract:
Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1 macrophages toward a transcriptional state reminiscent of disease-associated microglia and lipid-associated macrophages (LAM), collectively referred to as DLAM. Transcriptome profiling reveals gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing shows an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrate alterations in cell motility, phagocytosis, lysosomal activity, and metabolic profiles. These findings provide insights into cytokine-mediated reprogramming of macrophages toward disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.
Insights
Researchers reprogrammed human macrophages using a cytokine mix to mimic disease-associated states found in Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Myeloid cells, including microglia and macrophages, are crucial in neurodegenerative diseases like Alzheimer's disease (AD).
- Current in vitro models struggle to accurately represent the complex disease-associated states of these myeloid cells.
- Understanding these states is vital for developing effective AD therapies.
Purpose of the Study:
- To investigate the potential of a specific cytokine mix to reprogram human THP-1 macrophages into AD-relevant phenotypes.
- To establish a more robust in vitro model for studying myeloid cell roles in neurodegeneration.
Main Methods:
- Human THP-1 macrophages were treated with a cytokine cocktail (interleukin-4, CSF1, IL-34, and transforming growth factor-β).
- Transcriptome profiling (RNA sequencing) was employed to analyze gene expression changes.
- Single-cell RNA sequencing was used to assess cellular heterogeneity.
- Functional assays were conducted to evaluate changes in cell motility, phagocytosis, lysosomal activity, and metabolism.
Main Results:
- Cytokine treatment induced significant transcriptomic shifts, creating a phenotype termed DLAM (disease-associated microglia and lipid-associated macrophages).
- DLAM cells exhibited transcriptional profiles similar to disease-associated microglia and lipid-associated macrophages.
- Key changes were observed in oxidative phosphorylation, lysosome function, and lipid metabolism pathways.
- Functional assays confirmed altered cell motility, phagocytosis, lysosomal activity, and metabolic profiles in treated macrophages.
Conclusions:
- Cytokine-mediated reprogramming offers a viable method to generate AD-relevant myeloid cell phenotypes in vitro.
- This approach enhances our understanding of myeloid cell involvement in neurodegenerative processes.
- The developed DLAM model holds potential for future therapeutic development in Alzheimer's disease and related conditions.
