Scientists map the signals that turn monocytes into lipid-handling macrophages

Lipid-associated macrophages, or LAMs, are immune cells that accumulate in metabolically diseased tissues and in tumours, where they are recognised by marker genes and proteins such as GPNMB, SPP1 and TREM2. Cell fate tracing in living animals has shown that these cells are recruited to diseased lesions from pools of circulating monocytes, yet the intracellular signalling pathways and transcriptional regulators that drive the transition from monocyte to LAM have remained poorly understood, largely because LAMs are difficult to isolate and reliable laboratory models were lacking. A new open-access study published in Cell Communication and Signaling now reports a simple in vitro model that reproduces key features of this transition and uses it to dissect the signalling cascade step by step.

The research team, led by Ruonan Xu, Sarah Enzenhofer and senior author Andreas Prokesch, tested LAM marker expression in the monocytic cell lines THP-1 and U937 as well as in primary monocytes, including mouse bone marrow-derived cells and human monocytes derived from peripheral blood. When the cell lines were treated with phorbol 12-myristate 14-acetate, or PMA, a potent activator of protein kinase C (PKC), the cells strongly upregulated LAM marker genes at both the mRNA and protein levels. Crucially, this marker pattern mirrored the LAM expression profile observed in vivo in a mouse model of steatohepatitis, suggesting that the cultured cells capture a biologically relevant state rather than an artefact of the dish.

Pharmacological experiments pinpointed PKC as the engine of the transition. Inhibiting PKC completely repressed both cell adhesion and LAM marker expression, indicating that the kinase sits at the top of the pathway. Functionally, PKC activity proved necessary for several hallmark behaviours of these macrophages: storing triglycerides when the cells were loaded with lipid, maintaining effective lysosomal acidification, and carrying out phagocytosis. The authors assessed these lipid-handling and lysosomal functions with biochemical assays, tying the signalling pathway directly to the cellular specialisations that define LAMs.

Downstream of PKC, the study identified two further signalling branches. Focal adhesion kinase (FAK) and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) axis regulated adhesion and sustained LAM marker expression over time. At the transcriptional level, the work distinguished two layers of control: nuclear factor-kappa B (NF-κB) was found to be crucial for general macrophage differentiation, while peroxisome proliferator-activated receptor gamma (PPARG) emerged as one player within the broader transcriptional network that regulates the LAM-specific programme. These roles were evaluated using public datasets, a reporter cell line and specific inhibitors.

A particularly striking finding came from primary cells. In both mouse and human monocytes, FAK-dependent adherence to culture plates alone was sufficient to drive strong upregulation of LAM markers, meaning that a simple mechanical cue, sticking to a surface, can trigger much of the differentiation programme. This offers an unusually accessible experimental handle: researchers can now generate LAM-like cells from primary monocytes without complex differentiation cocktails, and manipulate individual signalling nodes with inhibitors to probe how the disease-associated state is maintained.

The authors present the work as both a model and a map. The model, comprising cell lines and primary monocytes that display high expression of genes defining the LAM phenotype, removes a long-standing bottleneck in the field, since detailed study of LAM development from circulating monocytes had been hampered by the absence of suitable culture systems. The map lays out the sequence from PKC activation through FAK and PI3K/AKT signalling to the NF-κB- and PPARG-dependent transcriptional programme that installs the LAM identity.

Because lipid- and tumour-associated macrophages are especially abundant among the immune cells infiltrating metabolically diseased tissues and cancers, and their numbers increase with disease progression, the ability to study them in a dish could have practical consequences. The researchers suggest the system may help identify new ways to manipulate these disease-associated immune cells, with the long-term aim of positively affecting disease outcomes. As with any in vitro model, findings in cultured cells will need to be tested in living systems, and the study is an accepted manuscript shared early ahead of the final version of record. Even so, by connecting an everyday laboratory manipulation to the molecular circuitry of a disease-relevant macrophage state, the work gives researchers a defined starting point for dissecting how monocytes become the lipid-laden macrophages that populate fatty liver disease and tumours.

Subject of Research: Signalling pathways controlling the transition of monocytes into lipid-associated macrophage-like cells

Article Title: Signalling pathways governing the transition from monocytes to a lipid-associated macrophage-like state

Article References: Xu, R., Enzenhofer, S., Ujwary, S., Zopf, V., Mukherjee, S., Slaats, E., Michenthaler, H., Strobl, H., Schindlmaier, K., Leithner, K., Krstic, J., Scott, C. L., Kratky, D., & Prokesch, A. (2026). Signalling pathways governing the transition from monocytes to a lipid-associated macrophage-like state. Cell Communication and Signaling. https://doi.org/10.1186/s12964-026-03318-9

Image Credits: AI Generated

DOI: 10.1186/s12964-026-03318-9

Keywords: lipid-associated macrophages, monocytes, PKC signalling, FAK, PI3K/AKT, NF-kB, PPARG, macrophage differentiation, steatohepatitis, in vitro model, THP-1, phagocytosis