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Characterization of prostate macrophage heterogeneity, foam cell markers, and CXCL17 upregulation in a mouse model of steroid hormone imbalance. | LitMetric

AI Article Synopsis

  • Benign prostatic hyperplasia (BPH) is a common age-related condition causing severe urinary issues, linked to hormonal imbalances such as elevated estradiol and testosterone levels.
  • Previous research in mice revealed that these hormonal changes lead to increased macrophage accumulation in the prostate, where they transform into foam cells.
  • The current study identified specific macrophage subtypes and their gene expression signatures in response to hormone imbalance, while also finding that a protein called Cxcl17 might encourage macrophages to enter the prostate lumen.

Article Abstract

Benign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology is believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using a mouse steroid hormone imbalance model identified a specific increase in macrophages that migrated and accumulated in the prostate lumen where they differentiated into lipid-laden foam cells in mice implanted with testosterone and estradiol pellets, but not in sham animals. The current study focused on further characterizing the cellular heterogeneity of the prostate in this model as well as identifying the specific transcriptomic signature of the recruited foam cells. Moreover, we aimed to identify epithelia-derived signals that drive macrophage infiltration and luminal translocation. Male C57BL/6J mice were implanted with slow-release testosterone and estradiol pellets (T + E2) or sham surgery was performed and the ventral prostates were harvested two weeks later for scRNA-seq analysis. We identified Ear2 + and Cd72 + macrophages that were elevated in response to steroid hormone imbalance, whereas a Mrc1 + resident macrophage population did not change. In addition, an Spp1 + foam cell cluster was almost exclusively found in T + E2 mice. Further markers of foam cells were also identified, including Gpnmb and Trem2, and GPNMB was confirmed as a novel histological marker with immunohistochemistry. Foam cells were also shown to express known pathological factors Vegf, Tgfb1, Ccl6, Cxcl16 and Mmp12. Intriguingly, a screen for chemokines identified the upregulation of epithelia-derived Cxcl17, a known monocyte attractant, in T + E2 prostates suggesting that it might be responsible for the elevated macrophage number as well as their translocation to the lumen. Our study identified macrophage subsets that responded to steroid hormone imbalance as well as further confirmed a potential pathological role of luminal foam cells in the prostate. These results underscore a potential pathological role of the identified prostate foam cells and suggests CXCL17-mediated macrophage migration as a critical initiating event.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383972PMC
http://dx.doi.org/10.1038/s41598-024-71137-4DOI Listing

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