Public-Data Reanalysis Links MS4A4A to M2-like Human Myeloid States and Supports a Predicted Four-Pass Transmembrane Fold

Research reexamining public human datasets has found a link between the MS4A4A gene and M2-like macrophage states in humans. MS4A4A is known to be associated with M2-like macrophages, and the MS4A gene cluster is known to influence soluble TREM2 levels and risk of Alzheimer's disease. The study aimed to determine if MS4A4A consistently marks the M2 side of human myeloid activation and whether AlphaFold, a protein structure prediction tool, supports a proposed interaction between MS4A4A and MS4A6A.

The researchers analyzed four public datasets, including bulk RNA-seq and ATAC-seq of primary monocyte-derived macrophages from three independent donors, as well as single-cell RNA-seq atlases of healthy liver and severe COVID-19 blood. They found that MS4A4A was significantly higher in M2 macrophages compared to M1 macrophages, with a log2 fold change of +2.68 and an adjusted P-value of 0.0013. The promoter region of MS4A4A also showed the highest mean accessibility in M2 macrophages.

Furthermore, MS4A4A was enriched in liver macrophages and monocyte-enriched in blood samples. In liver macrophages, MS4A4A was detected in 76.7% of M2-like macrophages, compared to 39.3% of M1-like macrophages. This difference was primarily driven by the proportion of positive cells. However, when AlphaFold was used to model the four transmembrane helices of MS4A4A, its predicted interface with MS4A6A was not supported, with an ipTM score of 0.59.

The study concludes that MS4A4A is consistently associated with the M2 side of human myeloid activation across different types of transcribed, chromatin, and single-cell datasets. However, the proposed interaction between MS4A4A and MS4A6A remains an untested structural hypothesis.