A mouse model of chronic prostatic inflammation using a human prostate cancer‐derived isolate of Propionibacterium acnes

Abstract

BACKGROUND Prostatic inflammation has been linked to a number of prostatic diseases such as benign prostatic hyperplasia (BPH), prostatitis syndromes, and prostate cancer. Major unanswered questions include what pathogenic mechanisms, such as bacterial infections, may drive the accumulation of inflammatory infiltrates in the human prostate, and how inflammation might contribute to disease. To study this potential link in an in vivo system, we developed a mouse model of long-term bacteria-induced chronic inflammation of the prostate using a human prostatectomy-derived strain of Propionibacterium acnes. METHODS C57BL/6J mice were inoculated, via urethral catheterization, with vehicle control or a prostatectomy-derived strain of P. acnes (PA2). Animals were assessed at 2 days, 1, 2, or 8 weeks post-inoculation via histology and immunohistochemistry (IHC). RESULTS PA2 inoculation resulted in severe acute and chronic inflammation confined to the dorsal lobe of the prostate. Chronic inflammation persisted for at least 8 weeks post-inoculation. Inflammatory lesions were associated with an increase in the Ki-67 proliferative index, and diminished Nkx3.1 and androgen receptor (AR) production. Interestingly, the observed response required live bacteria and both IHC and in situ hybridization assays for P. acnes indicated a potential intracellular presence of P. acnes in prostate epithelial cells. CONCLUSIONS To our knowledge, this is the first mouse model of long-term prostatic inflammation induced by P. acnes, and more generally, any prostatectomy-derived bacterial isolate. This model may serve as a valuable preclinical model of chronic prostatic inflammation that can be used to mechanistically study the link between inflammation and prostatic disease.

Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor

“…We demonstrate directly in vivo that attenuation of luminal epithelial AR signaling is capable of inducing prostate inflammation. On the other hand, inflammation has also been shown to suppress expression of AR and critical enzymes for testosterone metabolism (Debelec-Butuner et al, 2014; Khalili et al, 2010; Shinohara et al, 2013; Simons et al, 2014; Vignozzi et al, 2012a). Together, these results suggest a mutual induction between prostate inflammation and reduced luminal AR expression and imply the existence of a vicious cycle of prostate inflammation enforced by declining epithelial AR signaling.…”

Role of inflammasomes and their regulators in prostate cancer initiation, progression and metastasis

“…Characterization of the function of NLR family members in the initiation and progression of prostate cancer has potential for the development of new therapeutic strategies and interventions, especially for the effective management of hormone-resistant prostate cancer. Recent studies focused on the ubiquitous bacterium Propionibacterium acnes discovered that it could cause chronic prostatic inflammation [42,43]. P. acnes was also found to be involved in the maturation of IL-1 and IL-18 in the neutrophils through the activation of caspase-1 [44].…”

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer

“…15-19 The recent discovery of a urinary microbiome sheds new light on the possibility of frequent exposure of the prostate to a diverse number of microorganisms due to anatomical proximity, eg the urethra runs through the prostate and the prostatic ducts feed into the prostatic urethra. Therefore, the urinary tract may serve as a route of exposure of the prostate to microorganisms contained in the urethra.…”