Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia

Macrophages exhibit marked phenotypic heterogeneity within and across disease states. Lipid metabolic reprogramming critically regulates macrophage activation. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate as prostate size increases. No T cell subclusters specifically accumulate in large versus small prostates. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and prostatic symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages localize to the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define new BPH immune subpopulations, TREM2+ and MARCO+ macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.