Steroid hormone imbalance drives macrophage infiltration and Spp1/osteopontin⁺ foam cell differentiation in the prostate

Abstract

Benign prostatic hyperplasia (BPH) occurs progressively with aging in men and drives deteriorating symptoms collectively known as lower urinary tract symptoms (LUTS). Age‐associated changes in circulating steroid hormones, and prostate inflammation have been postulated in the etiology of BPH/LUTS. The link between hormones and inflammation in the development of BPH/LUTS is conflicting because they may occur independently or as sequential steps in disease pathogenesis. This study aimed to decipher the prostatic immune landscape in a mouse model of lower urinary tract dysfunction (LUTD). Steroid hormone imbalance was generated by the surgical implantation of testosterone (T) and estradiol (E2) pellets into male C57BL/6J mice and gene expression analysis was performed on ventral prostates (VPs). These experiments identified an increase in the expression of macrophage markers and Spp1/osteopontin (OPN). Localization studies of OPN pinpointed that OPN+ macrophages travel to the prostate lumen and transition into lipid‐accumulating foam cells. We also observed a significant increase in the number of tissue macrophages in the VP which was prevented in OPN‐knockout (OPN‐KO) mice. In contrast, mast cells, but not macrophages, were significantly elevated in the dorsal prostate of T + E2‐treated mice which was diminished in OPN‐KO mice. Steroid hormone implantation progressively increased urinary frequency, which was ameliorated in OPN‐KO mice. Our study underscores the role of age‐associated steroid hormone imbalances as a mechanism of expanding the prostatic macrophage population, their luminal translocation, and foam cell differentiation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Prostate Cell Heterogeneity and Cxcl17 Upregulation in Mouse Steroid Hormone Imbalance

“…Our previous study, 15 as well as the current analysis, highlighted that steroid hormone imbalance drives monocyte infiltration to the prostate as well as the translocation of macrophages to the prostate lumen where they differentiate into foam cells. In order to assess how resident prostate cells drive remodeling of the immune environment, we visualized the cytokine expression profile across epithelial, fibroblast and endothelial clusters in T+E2 treated versus control cells (Fig.…”

“…Fibroblast 2 and 3 were mainly localized to the subepithelial region and may potentially be subtypes of the "ductal fibroblasts" identified by Joseph et al 27 Most importantly, we found the highest expression of collagen genes in Fibroblast 3 cells emphasizing that this cell type could be a driver of prostatic fibrosis in the advanced stages of this model. 15 Our future studies will confirm this hypothesis in more chronic stages of the model. The lack of smooth muscle cells in our dataset is potentially due to the digestion protocol selected (cold protease), which will be adjusted in the future to retain these cells.…”

“…12,13 To further decipher this connection, our group has previously utilized a mouse model of steroid hormone imbalance that is created by the subcutaneous implantation of slow-release testosterone and estradiol pellets. 14,15 We found that macrophages were the primary type of immune cell to be significantly increased in this model, with the ventral prostate lobe experiencing the most substantial rise. 15 Most importantly, we identified that macrophages migrate to the lumen in both the mouse model and human BPH and take up lipids and adopt the foam cell phenotype.…”

“…14,15 We found that macrophages were the primary type of immune cell to be significantly increased in this model, with the ventral prostate lobe experiencing the most substantial rise. 15 Most importantly, we identified that macrophages migrate to the lumen in both the mouse model and human BPH and take up lipids and adopt the foam cell phenotype. 15 However, their significance in BPH progression remains largely unclear.…”

“…42 Cells with similar marker gene signature have been identified as interstitial macrophages that respond to LPS treatment 43 and may represent the pro-inflammatory macrophage subset we identified in an earlier study based on iNOS expression. 15 Conversely, Mac Ear2+ (myeloid 2) cells carry Retnla universal and Ear2 monocyte-derived alternatively activated (M2) macrophage markers. 31,32 Mac Spp1+ cells were delineated in our prior study as intraluminal foamy macrophages in this model, setting the stage for the goal of our current study to further elucidate their characteristics.…”