Immune dysregulation in the prostates of C57BL/6 ^Aire-/- 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 Aire transcription 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/6 ^Aire-/- mice were subcutaneously injected with prostate homogenate protein and Freund’s 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/6 ^Aire-/- mice. Histological and scRNA-seq data show that the dominant leukocyte phenotypes in the prostates of C57BL/6 ^Aire-/- mice are B and T lymphocytes. Macrophages in C57BL/6 ^Aire-/- 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 ⁺ GZMK hi GZMB low T cells in C57BL/6 ^Aire-/- prostates similar to those seen in human BPH. Further, fibroblast clusters in C57BL/6 ^Aire-/- 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/6 ^Aire-/- mice resemble human BPH, making this model useful for studying the impact of inflammation-driven prostatic hyperplasia.