Kolliegbo, A. K. | Search bioRxiv

bioRxiv2025

Immune dysregulation in the prostates of C57BL/6Aire-/- mice mirrors that seen in human benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is the most common urologic disease in aging men, resulting in significant morbidity. The etiologies of BPH are unknown, though chronic prostatic inflammation is known to promote hyperplasia, fibrotic remodeling, and therapeutic resistance in BPH. BPH is highly complex and heterogeneous, presenting with varying degrees of stromal and epithelial proliferation, fibrosis, inflammation and associated lower urinary tract symptoms. This complexity presents challenges in developing models. Here, we characterize an Airetranscription factor-deficient non-resolving (chronic) inflammation model in a C57BL/6J background for the study of the prostatic inflammation present in BPH. This chronic inflammatory model exhibits a lack of central tolerance but retains an otherwise intact and functional immune system. C57BL/6Aire-/-mice were subcutaneously injected with prostate homogenate protein and Freunds Complete Adjuvant and boosted after 10 days. After 21 and 35 days, whole prostates were collected for histology, flow cytometry, and scRNA-seq, which were then compared to human BPH scRNA-seq data Inflammation was confined to the prostate in C57BL/6Aire-/-mice. Histological and scRNA-seq data show that the dominant leukocyte phenotypes in the prostates of C57BL/6Aire-/-mice are B and T lymphocytes. Macrophages in C57BL/6Aire-/-mouse prostates express signatures associated with an array of phenotypes as also seen in BPH. We identify a Trem2+population of macrophages, and aging-associated Cd8+GZMKhi GZMBlow T cells in C57BL/6Aire-/-prostates similar to those seen in human BPH. Further, fibroblast clusters in C57BL/6Aire-/-are similar to fibroblasts identified from the prostates of patients diagnosed with BPH, and these clusters also express markers associated with aging. Overall, the inflammation and predicted interactions between leukocytes and stromal cells observed in the prostates of C57BL/6Aire-/-mice resemble human BPH, making this model useful for studying the impact of inflammation-driven prostatic hyperplasia.

immunology↗

bioRxiv2024

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, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. 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 preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate with increased prostate volume. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within 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 two 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.

immunology↗