RT Journal Article SR Electronic T1 Cytokine-induced reprogramming of human macrophages toward Alzheimer’s disease-relevant molecular and cellular phenotypes in vitro JF bioRxiv FD Cold Spring Harbor Laboratory SP 2024.10.24.619910 DO 10.1101/2024.10.24.619910 A1 Podlesny-Drabiniok, Anna A1 Romero-Molina, Carmen A1 Patel, Tulsi A1 See, Wen Yi A1 Liu, Yiyuan A1 Marcora, Edoardo A1 Goate, Alison M. YR 2024 UL http://biorxiv.org/content/early/2024/10/29/2024.10.24.619910.abstract AB Myeloid cells including brain-resident (microglia) and peripheral macrophages play a crucial role in various pathological conditions, including neurodegenerative disorders like Alzheimer’s disease (AD). They respond to disruption of tissue homeostasis associated with disease conditions by acquiring various transcriptional and functional states. Experimental investigation of these states is hampered by the lack of tools that enable accessible and robust reprogramming of human macrophages toward Alzheimer’s disease-relevant molecular and cellular phenotypes in vitro. In this study, we investigated the ability of a cytokine mix, including interleukin-4 (IL4), colony stimulating factor 1 (CSF1/MCSF), interleukin 34 (IL34) and transforming growth factor beta (TGFβ), to induce reprogramming of cultured human THP-1 macrophages. Our results indicate this treatment led to significant transcriptomic changes, driving THP-1 macrophages towards a transcriptional state reminiscent of disease-associated microglia (DAM) and lipid-associated macrophages (LAM) collectively referred to as DLAM. Transcriptome profiling revealed gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing revealed an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrated alterations in cell motility, phagocytosis, lysosomal activity, and metabolic and energetic profiles. Our findings provide insights into the cytokine-mediated reprogramming of macrophages towards disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.Competing Interest StatementA.M.G.: Scientific Advisory Board (SAB) Genentech; SAB Muna Therapeutics; E.M.: consultant Dorian Therapeutics, Turn Biotechnologies.