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. Author manuscript; available in PMC: 2014 Apr 18.
Published in final edited form as: Prostate. 2013 Feb 6;73(9):1007–1015. doi: 10.1002/pros.22648

A Mouse Model of Chronic Prostatic Inflammation Using a Human Prostate Cancer-Derived Isolate of Propionibacterium acnes

Debika Biswal Shinohara 1, Ajay M Vaghasia 2, Shu-Han Yu 3, Tim N Mak 4, Holger Brüggemann 4, William G Nelson 1,2,3, Angelo M De Marzo 2,3, Srinivasan Yegnasubramanian 1,2, Karen S Sfanos 2,3,*
PMCID: PMC3991131  NIHMSID: NIHMS563214  PMID: 23389852

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.

Keywords: prostate, Propionibacterium acnes, inflammation, mouse model

INTRODUCTION

Asymptomatic prostatic inflammation (i.e., “histological prostatitis”) is a nearly universal finding in the prostate of the adult male in the developed world, as evidenced by studies examining men who undergo biopsy for prostate cancer due to elevated prostate-specific antigen (PSA) levels and test negative for cancer [1–4], autopsy studies [5], and findings from transurethral resections for benign prostatic hyperplasia (BPH) [6]. Furthermore, prostatic inflammation has been linked to arguably all major diseases of the human prostate including BPH, prostatitis syndromes, and prostate cancer [7–10]. The major questions that remain to be answered regarding the pathogenic role of inflammation in prostatic disease are (1) what events, such as bacterial infections, drive the accumulation of inflammatory infiltrates in the human prostate, and (2) what are the mechanism(s) by which inflammation might contribute to prostatic disease.

Propionibacterium acnes (P. acnes) is an anaerobic, gram-positive bacterium that is found nearly ubiquitously on human skin. Although typically regarded as a human commensal, P. acnes is a highly pro-inflammatory bacterium that is implicated as the causative agent in the skin disease acne vulgaris, and in inflammatory conditions such as endocarditis, sarcoidosis, and post-surgical infections [11]. Interestingly, P. acnes has been identified in prostate-derived tissues and has been associated with prostate cancer in molecular and epidemiological studies [12–17]. Recently, P. acnes was reported as the predominant bacterium detected in tissues from patients with BPH [18] and prostate cancer [19]. Intriguingly, in the latter study, the ability to culture P. acnes was strongly correlated with prostatic inflammation in prostatectomy tissues [19]. Furthermore, in vitro studies demonstrated that P. acnes was capable of inducing a strong inflammatory response in prostate-derived cell lines [14,20,21]. However, the presence of this organism in the prostate has also been questioned as a potential contaminant, as it is a predominant member of the commensal skin microflora and often reported as a culture contaminant [22]. Providing evidence against this, multilocus sequence typing (MLST) analysis of prostatectomy-derived isolates of P. acnes demonstrated that prostate-derived P. acnes strains do not fall within the typical skin/acne sequence types (STs), but rather are characteristic of STs associated with opportunistic infections and/or urethral flora [23]. However, no study has firmly established a causal role for P. acnes in the acute or chronic inflammation often observed in the prostate.

To date, most published studies of prostatic infection conducted in mice have utilized uropathogenic strains of E. coli, are performed in rare strains of mice, and/or have only been carried out for a few days or ≤2 weeks [24–27]. As a means to begin to address the potential role of P. acnes as a pro-inflammatory stimulus in the prostate, as well as to develop an in vivo system to study the role of long-term bacteria-induced prostatic inflammation in prostatic disease, we developed a model of P. acnes infection of the prostate in wild-type C57BL/6J mice. We report that inoculation with a human prostatic isolate of P. acnes (PA2) [23] is capable of inducing acute and chronic inflammation in the dorsal lobe of the mouse prostate, with persistence of the chronic inflammation for at least 8 weeks. Chronic inflammation is accompanied by increased epithelial proliferative fraction and decreased Nkx3.1 and androgen receptor (AR) protein levels, findings that have been reported previously in association with prostatic inflammation in another E. coli based model of short-term infection in the mouse prostate [26]. Our findings establish a causative relationship between prostatectomy-associated strains of P. acnes and prostatic inflammation. This mouse model of infection-induced chronic inflammation may serve as a valuable in vivo model to study inflammation-associated prostatic diseases such as BPH, prostatitis and prostate cancer.

METHODS

Animals

All procedures were performed on 8–10-week-old C57BL/6J wildtype mice under the guidelines of the Johns Hopkins Animal Care and Use Committee (ACUC) and with an approved animal protocol. Mice were housed in a pathogen-free environment, allowed free access to food and water, and were maintained on a 12 hr light/dark cycle. Mice were sacrificed via CO2 asphyxiation and serum was collected by cardiac puncture. Seminal vesicles, urinary bladder, anterior, dorsal/lateral, and ventral prostate lobes were collected along with other reference organs.

Transurethral Catheterization and Inoculation of P. acnes

Mice were anaesthetized with ketamine/xylazine and then catheterized via the urethra using lubricated sterile polyethylene catheters (PE-10 tubing, BD Biosciences) 2.5 cm in length. Inoculation of a prostatectomy-derived strain of P. acnes (PA2) [23] into the bladder and prostate was performed with a PA2 dose of approximately 107 colony forming units (CFU) in a 20 μl volume. PA2 belongs to CC36, a clonal complex of P. acnes that is associated with opportunistic infections [23]. Of interest, the PA2 strain was isolated from a radical prostatectomy specimen that contained both acute and chronic inflammation (Supplementary Fig. 1). Control animals were inoculated with an equal volume of sterile phosphate buffered saline (PBS, vehicle control) or heat-killed PA2 (heated at 60°C for 1 hr).

Prostate Histopathology and Assessment of Inflammation

Prostate lobes were dissected separately into anterior, dorsal/lateral, and ventral lobes and placed into formalin. All tissues were fixed in 10% buffered formalin for 48 hr before paraffin embedding. Hematoxylin and eosin (H&E) staining was performed using the Leica Microsystems AutoStainer XL (Buffalo Grove, IL). Slides were scanned at 20× using the Aperio ScanScope (CS model, Aperio, Vista, CA) and viewed using the freeware ImageScope Viewer Software (Aperio version 10.2.2.2353). Total dorsal prostate area, total inflamed area, and grade of inflammation (mild, moderate, and severe), were evaluated in a manner such that the evaluator was blinded to the treatment group of the animal. Total percentage of inflamed area was calculated as the total area of inflamed prostate divided by the total area of dorsal prostate using the ImageScope Viewer Software. For inflammation grading, prostate tissues were considered positive for mild inflammation if scattered neutrophilic or mononuclear inflammatory cells were present and involved multiple glands/foci. Prostate tissues were considered to be moderately inflamed if clusters (but not follicles) of lymphocytes and/or macrophages were present and involved multiple glands/foci. Prostate tissues were considered to be severely inflamed if dense nodules/follicles of inflammatory cells were present.

Immunohistochemistry

Slides containing sections of formalin-fixed, paraffin-embedded (FFPE) mouse prostate tissues were deparaffinized in xylene and rehydrated through a series of graded ethanol. For androgen receptor (AR) and P. acnes antibody IHC, slides were steamed for 45 min (AR antibody) or 17 min (P. acnes antibody) in high temperature target retrieval solution for antigen retrieval (Dako Cytomation). For Ki-67 IHC, slides were steamed for 25 min in citrate buffer (Vector Laboratories). For Nkx3.1 IHC, slides were steamed in 1 mmol/L EDTA (pH 8.0) for 45 min. For P. acnes antibody staining, slides were digested with 1 mg/ml lysozyme (Sigma Aldrich) for 25 min at 37°C followed by digestion with achromopeptidase (30 U/ml, Sigma Aldrich) for 25 min at 37°C and blocking with 5% donkey serum for 10 min at room temperature. Slides were then incubated with primary antibodies for AR (Santa Cruz Biotechnology) at a dilution of 1:1,000 for 1 hr at room temperature, Ki-67 (Novocastra) at a dilution of 1:1,200 for 1 hr at room temperature, Nkx3.1 [28] at a dilution of 1:6,000 overnight at 4°C, or P. acnes antibody [14] at a dilution of 1:2,000 overnight at 4°C, followed by incubation with secondary antibody (Powervision, Leica Microsystems) for 45 min at room temperature. Staining was visualized using 3,3′-Diamino-benzidine (Sigma FAST 3,3′-Diamino-benzidine tablets), and slides were counterstained with hematoxylin.

In Situ Hybridization (ISH)

ISH was performed on FFPE mouse dorsal prostate tissues using the RNAscope 2.0 FFPE Brown Reagent Kit (Advanced Cell Diagnostics, Inc.) and a custom RNAscope target probe designed against the P. acnes 16S rRNA gene.

RESULTS

P. acnes Inoculation Induces Acute and Chronic Inflammation in the Mouse Prostate

Anaesthetized C57BL/6J mice between 8 and 10 weeks of age were inoculated transurethrally with PBS or 107 CFU of prostatectomy-derived P. acnes (PA2) [23] in a volume of 20 μl. Mice from each group (n = 2 for PBS controls, n = 5 for PA2 treated animals) were sacrificed 2 days, 1,2, or 8 weeks post-inoculation. Prostatic inflammation was never observed in PBS treated controls at any time point or tissue analyzed (Fig. 1). In contrast, in PA2 inoculated animals, the dorsal prostate lobe selectively developed acute and chronic inflammation in a distinct time-course. While at 2 days post-inoculation there was an absence of any inflammation, at 1 week there was a dense accumulation of neutrophils primarily in glandular lumens along with dense clusters or follicles of mononuclear inflammatory cells in the stroma (Fig. 1). Although a sparse neutrophilic glandular infiltrate was still present in a subset of animals, by 2 weeks post-infection, the inflammatory infiltrates were primarily chronic inflammation (lymphocytes and macrophages) observed as dense follicles in the stroma. While this severe chronic inflammation began to subside somewhat with time, mild to moderate chronic inflammatory infiltrates persisted even at 8 weeks after P. acnes inoculation (Fig. 1). Interestingly, histological examination of genitourinary tissues revealed that the bladder, anterior prostate, and ventral prostate were unaffected by PA2 inoculation at all time-points analyzed. In order to determine whether the selectivity for inflammation in the dorsal lobe may be due to selectivity in the distribution of the inoculum, we performed transurethral inoculations with crystal violet dye to visualize its localization. Immediate sacrifice and examination revealed the presence of dye exclusively in the dorsal prostate lobes and the urinary bladder (Supplementary Fig. 2). Thus, it appears that that the localization of inflammation in the dorsal lobe is reflective of the route of inoculation and not necessarily any lobe predilection to infection with P. acnes.

Fig. 1.

Fig. 1

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Dorsal prostate of C57BL/6J mice 1,2, or 8 weeks after inoculation of either PBS (control) or PA2 P. acnes via urethral catheterization. Accumulations of neutrophils were observed in the glandular lumens (arrows) at 1 and 2 weeks post-inoculation. Accumulations of chronic inflammatory cells in the stroma (arrowheads) were observed at all time points starting at 1 week post-inoculation. Bottom row is enlarged view of boxed area in panel above.

While acute inflammation is often reported to be observed within 48 hr of inoculation in multiple rodent models of E. coli-induced bacterial prostatitis [24,29,30], we did not observe the onset of acute or chronic inflammation until 1 week post-inoculation. Interestingly, the dorsal prostate exhibited variable degrees of inflammation among PA2 infected animals. By 1 week post-inoculation, three out of five of the animals inoculated with PA2 showed evidence of a severe inflammatory response predominated by dense accumulations of luminal neutrophils and stromal mononuclear inflammatory cells (Fig. 2A). At 2 and 8 weeks following inoculation, while the overall fraction of animals showing any inflammation remained at three out of five animals, there was a greater fraction of animals having mild or moderate inflammation (Fig. 2A). Among animals with inflamed dorsal prostates, on average, 58.6% of the total dorsal prostate area was affected 1 week post-inoculation, 26.2% was affected 2 weeks post-inoculation, and 20.2% was affected 8 weeks post-inoculation (Fig. 2B).

Fig. 2.

Fig. 2

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Prevalence (A) and extent (B) of inflammation in mouse dorsal prostate lobes after PA2 P. acnes infection.

P. acnes-Induced Prostatic Inflammation Requires Live Bacteria

To determine if live bacteria are required to induce inflammation, we inoculated heat-killed PA2 P. acnes into C57BL/6J mice (n = 7). No evidence of an inflammatory response was observed in mice that had been inoculated with heat-killed PA2 at 1 week post-inoculation, indicating that live bacteria are required for the onset of the inflammatory response.

P. acnes Cells Were Found in the Intra- and Extra-Cellular Space in the Setting of Acute, But Not Chronic Inflammation

In order to determine if the inflammation observed in the dorsal lobe of PA2 infected animals may relate to a continued presence of bacteria, we assayed for the presence of P. acnes in dorsal prostate tissues via IHC with a P. acnes-specific antibody [14] as well as P. acnes-specific RNA ISH. At both 1 and 2 weeks post-infection, P. acnes cells could be detected almost exclusively in areas of the dorsal prostate that contained prostate-infiltrating neutrophils (Fig. 3A–E). Interestingly, P. acnes cells were also detected in the intracellular space of the prostate epithelium of acutely inflamed glands (Fig. 3B–E). However, by 8 weeks post-inoculation, whole P. acnes cells were no longer detected in the dorsal prostate lobe (Fig. 3F), despite the persistence of chronic inflammation in most animals. The anti-P. acnes antibody and the ISH probe produced highly similar staining results.

Fig. 3.

Fig. 3

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Detection of P. acnes in mouse dorsal prostate. IHC (A,B) and 1SH (C) for P. acnes at I week post-inoculation. IHC for P. acnes 2 weeks post-inoculation (D,E) and 8 weeks post-inoculation (F). Note positive staining for P. acnes cells in prostate-infiltrating neutrophils (arrows pointing to representative examples) and prostate epithelium (arrowheads pointing to representative examples).

Prostate Glands Near P. acnes-Induced Inflammatory Lesions Have Increased Proliferative Index and Diminished Expression of Nkx3.1 and AR

To determine whether P. acnes-induced dorsal lobe inflammation was associated with an increase in cellular proliferation, we performed IHC with the proliferation-associated marker Ki-67. As shown in Figure 4, we only observed an increase in the number of cells positive for Ki-67 in inflamed prostatic ducts. This increase in Ki-67 positive cells in inflamed regions of the dorsal prostate was observed at 1, 2, and 8 weeks post-inoculation (Fig. 4).

Fig. 4.

Fig. 4

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Increased proliferative index of inflamed dorsal prostate. IHC for Ki-67 1, 2, and 8 weeks post-inoculation with PA2 P. acnes. Note increased Ki-67 nuclear staining in epithelium of inflamed glands (arrowheads) versus non-inflamed glands (arrows).

Nkx3.1 is commonly decreased in human proliferative inflammatory atrophy (PIA) lesions [31], and was recently reported to decrease in the setting of E. coli-induced bacterial prostatitis [26]. As such, it was of interest to investigate the status of Nkx3.1 in P. acnes-induced prostatic inflammation. While Nkx3.1 is typically uniformly expressed in prostate epithelium in all lobes of the prostate, there was a marked decrease in Nkx3.1 production in inflamed glands of the dorsal lobe at both 1 and 2 weeks post-inoculation with PA2 (Fig. 5). Androgen receptor is likewise typically uniformly expressed in both epithelial and stromal cells in all lobes of the mouse prostate and is decreased in PIA lesions in the human prostate [32] as well as in the E. coli prostatitis model [26]. We observed a focal down-regulation of AR in epithelial cells that was restricted to inflamed glands of the dorsal lobe of animals both 1 and 2 weeks after infection with PA2 (Fig. 5). The down-regulation observed for both Nkx3.1 and AR was most apparent at 1 and 2 weeks, as it was specifically associated with severely inflamed dorsal prostate (Fig. 2A).

Fig. 5.

Fig. 5

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IHC for Nkx3.1 and AR in P. acnes infected mouse dorsal prostate at I (top row) and 2 weeks (bottom row) post-inoculation. Note diminished Nkx3.1 and AR staining in epithelial cells of inflamed glands (arrowheads) versus non-inflamed glands (arrows).

DISCUSSION

While the exact causes of prostatic inflammation remain unclear, epidemiologic and histologic evidence support a role for bacterial infection. Pathogenic organisms that are known to infect and induce inflammation in the human prostate include E. coli and sexually transmitted organisms [9]. Recently, P. acnes was reported as the predominant bacterium detected in tissues from patients with BPH [18] and prostate cancer [19]. P. acnes is a highly pro-inflammatory bacterium that is implicated as the causative agent in the skin disease acne vulgaris and many other inflammatory conditions, including SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome [11]. Interestingly, P. acnes (previously named Corynebacterium parvum) was studied in the 1970s and 1980s with the hope of harnessing its proinflammatory nature as an immunostimulatory agent in the treatment of cancer [33,34].

In recent reports, the ability to culture P. acnes was strongly correlated with prostatic inflammation in prostatectomy tissues [19]. Furthermore, in vitro studies have demonstrated that P. acnes is capable of inducing a strong inflammatory response in prostate-derived cell lines [14,20,21]. In order to explore a potential causal connection between P. acnes and prostate inflammation, we have developed a novel mouse model of P. acnes inoculation/infection in the prostate. Using this model, we provide the first evidence that P. acnes can induce inflammation in the prostate in an in vivo mouse model. Inoculation of 107 CFU of prostatectomy-derived P. acnes (PA2) in a 20 μl volume into the C57BL/6J mouse prostate resulted in severe acute inflammation exclusively in the dorsal prostate lobe. Administration of crystal violet dye using the identical volume and urethral catheterization methods revealed that the inoculum selectively localizes to the dorsal prostate, accounting for the observed exclusivity of the infectious/inflammatory sequelae in the dorsal lobe. While using higher volumes of the inoculum (200 μl) has been reported to allow exposure of all prostate lobes, we wanted to avoid such high volumes since they were also associated with mechanical injury to the prostate, leading to infiltration of inflammatory cells, and induction of inflammatory cytokines even with instillation of just saline without any infectious inoculum [24].

In our model, we did not observe the onset of acute or chronic inflammation until 1 week post-inoculation, while acute inflammation is often reported to be observed within 48 hr of inoculation in other rodent models of E. coli-induced bacterial prostatitis [24,29,30]. This is consistent with in vitro observations of a delayed inflammatory response to P. acnes infection of prostate epithelial cells [21]. Intriguingly, we also observed evidence of intracellular P. acnes infection of mouse prostate epithelial cells. Since P. acnes is not typically known to be an intracellular pathogen, these observations will most certainly be the focus of future studies.

We observed variable degrees of inflammation in the dorsal prostates of PA2 infected animals. By 1 week post-inoculation, three out of five animals inoculated with PA2 showed evidence of a severe inflammatory response predominated by dense accumulation of luminal neutrophils and stromal mononuclear inflammatory cells. At 2 and 8 weeks following inoculation, the incidence of inflammation remained at three out of five animals; however the inflammatory response was less severe. Over time, the area of the prostate that was actively inflamed also decreased, although remodeled glands with thickened stroma were often found adjacent to these areas.

In addition to inducing an acute and chronic inflammatory response in the dorsal prostate, our model recapitulated molecular features of inflamed human prostate, including diminished expression of Nkx3.1 and androgen receptor in inflamed glands, as well as increased proliferation in epithelial cells of these glands. It has been previously reported that Ki-67 levels are increased and AR levels are decreased in association with human proliferative inflammatory atrophy (PIA), an inflammation-associated lesion in the prostate that is a suspected precursor lesion to prostatic intraepithelial neoplasia (PIN) and prostate cancer [32]. Furthermore, it has been proposed that Nkx3.1 may act as a tumor suppressor by protecting prostate epithelial cells from oxidative stress [35]. Consistent with this, Nkx3.1 expression is decreased in human prostate cancers [26]. Therefore, downregulation of this protein and enhanced proliferation of epithelial cells may provide an environment conducive to neoplastic transformation of epithelial cells and carcinogenesis. Further studies are currently underway to determine whether chronic inflammation induced by P. acnes can result in carcinogenesis in the prostate.

CONCLUSIONS

In conclusion, we have developed the first mouse model of chronic prostatic inflammation induced by a prostatectomy tissue-derived bacterial isolate. Furthermore, we provide the first causal evidence that P. acnes is capable of inducing inflammation in the mouse prostate. This preclinical in vivo model may prove valuable for studying the role of bacteria-induced chronic inflammation in prostate cancer initiation and/or progression. Finally, this mouse model of infection-induced chronic inflammation may also serve as a valuable in vivo model to study additional inflammation-associated prostatic diseases such as bacterial prostatitis and BPH.

Acknowledgments

Grant sponsor: The Johns Hopkins University Prostate Cancer SPORE; Grant number: 5P50CA058236; Grant sponsor: Prostate Cancer Foundation (PCF); Grant sponsor: NIH/NCI; Grant numbers: U54CA091409; R01CA070196; Grant sponsor: Howard-Hopkins Partnership; Grant sponsor: NIH; Grant number: P20DK090921; Grant sponsor: NIEHS Training; Grant number: ES07141.

This work was funded by: The Johns Hopkins University Prostate Cancer SPORE Grant (5P50CA058236) Young Investigator Award (to K.S.S.), the Chris and Felicia Evensen Prostate Cancer Foundation (PCF) Young Investigator Award (to K.S.S.), NIH/NCI grant U54CA091409 Howard-Hopkins Partnership Grant, NIH grant P20DK090921, and NIH/NCI grant R01CA070196. D.B.S is supported by NIEHS training grant ES07141. We would like to thank Dr. Charles Bieberich (UMBC) for use of the Nkx3.1 antibody for IHC.

Footnotes

Additional supporting information may be found in the online version of this article.

Disclosure Statement: A.M.D. is currently an employee of Predictive Biosciences, Inc. who also holds a part-time adjunct appointment at the Johns Hopkins University School of Medicine. However, no funding or other support was provided by the company for any of the work in this manuscript. The terms of the relationship between A.M.D. and Predictive Biosciences are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

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