CD8 T cells are dispensable for experimental autoimmune prostatitis induction and chronic pelvic pain development.

Introduction: Chronic Pelvic Pain Syndrome or Chronic Prostatitis (CPPS/CP) is the most prevalent urologic affliction among young adult men. It is a challenging condition to treat, which significantly decreases patient quality of life, mostly because of its still uncertain aetiology. In that regard, an autoimmune origin is a prominent supported theory. Indeed, studies in patients and in rodent models of Experimental Autoimmune Prostatitis (EAP) have provided compelling evidence suggesting a key role of CD4 Th1 cells in disease pathogenesis. However, the implication of other prominent effectors of the immune system, such as CD8 T cells, has yet to be studied. Methods: We herein analyzed the induction of prostatitis and the development of chronic pelvic pain in EAP using CD8 T cell-deficient animals. Results: We found similarly elevated PA-specific immune responses, with high frequencies of specific IFNg+CD4+ and IL17+CD4+ T cells in prostate draining lymph nodes from PA-immunized either CD8 KO or wild type animals with respect to controls. Moreover, these peripheral immune responses were paralleled by the development of significant chronic pelvic pain, and accompanied by prostate histological lesions, characterized by hemorrhage, epithelial cell desquamation, marked periglandular leukocyte infiltration, and increased collagen deposition in both, PA-immunized CD8 KO and wild type animals. As expected, control animals did not develop prostate histological lesions. Discussion: Our results indicate that CD8 T cells do not play a major role in EAP pathogenesis and chronic pelvic pain development. Moreover, our results corroborate the previous notion that a CD4 Th1 associated immune response drives the induction of prostate tissue inflammation and the development of chronic pelvic pain.

Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

CLTA-4 Expression is Associated with the Maintenance of Chronic Inflammation in Endometriosis and Infertility.

Altered immune mechanisms are implicated in the pathogenesis of endometriosis. CTLA-4 is a membrane receptor that favors the anergic state of lymphocytes, which may disrupt the immune system response in the endometriotic environment. In this study, we examined the expression of CTLA-4 on T and B cells by flow cytometry and its levels in blood serum and peritoneal fluid by ELISA. Levels of CTLA-4+ T cells were significantly higher in patients with more advanced endometriosis than in those with less advanced disease. Additionally, the negative correlation of CTLA-4+ T lymphocytes and the percentage of NK and NKT-like cells in women with endometriosis and infertility may indicate a different etiopathogenesis of endometriosis accompanying infertility. Our findings shed light on the potential of CTLA-4 in developing new diagnostic and therapeutic approaches in endometriosis management.

Is primary dysmenorrhea a precursor of future endometriosis development?

Primary dysmenorrhea (PD) is the most common gynecologic disorder during adolescence and it is characterized by crampy lower abdominal pain that occurs during menstruation. Secondary dysmenorrhea, in contrast, has the same clinical features but occurs in women with a disease that could account for their symptoms (endometriosis, adenomyosis, uterine fibroids, pelvic inflammatory disease). Endometriosis is the most common cause of secondary dysmenorrhea and it should be considered in patients with persistent and clinically significant dysmenorrhea despite treatment. It is often diagnosed after a long delay, increasing the likelihood of pain chronicity and fertility problems at a later age. Women who suffer from dysmenorrhea in adolescence have higher risk of endometriosis in future. The open question is if endometriosis was already present at the onset of dysmenorrhea but undiagnosed or if PD favors subsequent development of endometriosis-associated pain. Since PD is associated with higher risk for developing chronic pain state and shares some of the same pain pathways of endometriosis (prostaglandins overproduction, inflammation, peripheral sensitization, central sensitization and abnormal stress responses), a correlation between PD and endometriosis is suggested. To know whether it is a risk factor for the development of endometriosis-associated pain may provide an opportunity for early intervention and prevention. The present review aims to investigate the clinical and pathogenetic features of PD and endometriosis in order to identify a possible association between the two conditions.

Immunological alterations in patients with chronic prostatitis/chronic pelvic pain syndrome and experimental autoimmune prostatitis model: A systematic review and meta-analysis.

BACKGROUND: As one of the most common conditions in urological outpatients, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) puzzles many individuals because of its unclear etiology and lack of effective treatment. Recently, immunological alterations underpinning CP/CPPS have been extensively investigated. METHODS: The PubMed, Web of Science, Cochrane library, and EMBASE databases were used to search original articles on immune mediators in patients with CP/CPPS and in experimental autoimmune prostatitis (EAP) models through April 10, 2020. Standardized mean differences (SMD) were calculated to summarize the differences in immune mediator levels between groups. Funnel plot, Begg's funnel plot, Egger's regression test, and the sensitivity analysis were applied to determine and visualize the stability of our findings. RESULTS: A total of 34 original studies were included in the meta-analysis, including 24 studies on patients with CP/CPPS and 10 studies on EAP models. We found that TNF-α, IL-1ß, IL-6, and IL-8 were the four immune mediators that elevated in most of the samples derived from patients with CP/CPPS and the EAP models. The adjusted publication bias analysis indicated that publication bias was not existed, and the sensitivity analyses showed that the results were stable. CONCLUSIONS: Immune responses play significant roles during the pathogenesis of CP/CPPS by promoting intraprostatic inflammation. Our findings provide potential diagnostic and therapeutic targets for CP/CPPS patients.

T2 Peptide Represents a Major Autoantigen Epitope in Experimental Autoimmune Prostatitis.

Chronic prostatitis/chronic pelvic pain syndromes (CP/CPPS) is a clinical tricky problem due to its enigmatic etiology, low cure rate, and high recurrence rate. The research on its pathogenesis has never stopped. In this experimental autoimmune prostatitis (EAP) model, male C57BL/6 mice were subcutaneously immunized with prostate extracts in an adequate adjuvant. For mice in the antibody intervention group, anti-T2 polyclonal antibodies were intraperitoneally injected during the induction of EAP. Animals were periodically monitored for pelvic pain. Hematoxylin and eosin staining was used to assess prostate inflammation. Tumor necrosis factor-α (TNF-α) levels in serum were measured by ELISA kits. The immunized animals developed prostatitis as a consequence of the immune response against prostate antigens. Pelvic pain thresholds were gradually decreased and TNF-α expression significantly increased. T2 plays an important role in the disease since polyclonal antibodies to T2 greatly ameliorated symptoms in animals induced for EAP. T2 peptide may represent the major autoantigen epitope in EAP, which could serve for a better understanding of the etiology of CP/CPPS.

Does Pollen Trigger Urological Chronic Pelvic Pain Syndrome Flares? A Case-Crossover Analysis in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network.

PURPOSE: We sought to determine whether pollen triggers urological chronic pelvic pain syndrome flares. MATERIALS AND METHODS: We assessed flare status every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain case-crossover analysis of flare triggers (NCT01098279). Flare symptoms, flare start date and exposures in the 3 days before a flare were queried for the first 3 flares and at 3 randomly selected nonflare times. These data were linked to daily pollen count by date and the first 3 digits of participants' zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to nonflare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the 3 weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders. RESULTS: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (OR 1.31, 95% CI 1.04-1.66) and full longitudinal (RR 1.23, 95% CI 1.03-1.46) samples. CONCLUSIONS: We found some evidence to suggest that rising pollen count may trigger flares of urological chronic pelvic pain syndrome. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention and treatment, and control over the unpredictability of flares.

Serum macrophage migration inhibition factor for diagnosing endometriosis and its severity: case-control study.

BACKGROUND: Endometriosis is a long-standing progressive disease that affects women of reproductive age. Macrophage migration inhibitory factor (MIF) is one of non-invasive blood biomarker that was detected in sera of endometriotic patients. The present study aimed to determine the accuracy of serum MIF in diagnosing endometriosis in women with infertility and chronic pelvic pain, and correlate its level to the stage of the disease. METHODS: Observational case-control study conducted at Fayoum University hospital from March 2016 till September 2018. Three hundred women candidate for diagnostic laparoscopy for either infertility or gynecologic chronic pelvic pain were included. The study group included patients with symptoms suggestive of endometriosis or chocolate cyst by ultrasound and proved by laparoscopy and histopathology. The control group included other causes of infertility or pelvic pain. All patients undergone either diagnostic or operative laparoscopy, and before laparoscopy blood sampling for quantitative measurement of macrophage migration inhibitory factor (MIF) protein in serum by ELISA technique. RESULTS: The level of serum MIF was significantly higher in endometriosis group compared to control group (1.75 ± 1.48 pg/ml and 0.51 ± 0.45 pg/ ml, respectively, P = < 0.001), with a progressive increase with advancing stage (stage I, 1.3 ± 1.03 pg/ml, stage II, 1.7 ± 1.57 pg/ml, stage III, 2.1 ± 1.19 pg/ml and in stage IV, 3.2 ± 2.6 pg/ml). Moreover, in patients presented with pain and infertile patients showed significantly higher levels of serum MIF (1.92 ± 1.13 vs 1.21 ± 1.17 and 1.82 ± 1.13 vs 1.32 ± 0.91 respectively with p-value < 0.001). ROC curve of serum MIF with a cut off value of 0.85 pg/ml or more achieves a sensitivity of 80.6%, specificity of 83.3%, positive predictive value of 82.9% and negative predictive value of 81.2%. CONCLUSION: Serum MIF might be a promising marker not only for noninvasive diagnosis of endometriosis but as a target for detecting severity as well.

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function.

Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.

TRPV1 in experimental autoimmune prostatitis.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a disorder that is characterized by persistent pelvic pain in men of any age. Although several studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel is involved in various pathways of chronic pain, the TRPV1 channel has not been implicated in chronic pelvic pain associated with CP/CPPS. METHODS: Male C57BL/6J (B6) and TRPV1 knockout (TRPV1 KO) mice (5-7 weeks old) were used to study the development of pelvic allodynia in a murine model of CP/CPPS called experimental autoimmune prostatitis (EAP). The prostate lobes, dorsal root ganglia (DRG), and spinal cord were excised at day 20. The prostate lobes were assessed for inflammation, TRPV1 expression, and mast cell activity. DRG and spinal cord, between the L6-S4 regions, were analyzed to determine the levels of phosphorylated ERK1/2 (p-ERK 1/2). To examine the therapeutic potential of TRPV1, B6 mice with EAP received intraurethral infusion of a TRPV1 antagonist at day 20 (repeated every 2 days) and pelvic pain was evaluated at days 20, 25, 30, and 35. RESULTS: Our data showed that B6 mice with EAP developed pelvic tactile allodynia at days 7, 14, and 20. In contrast, TRPV1 KO mice with EAP do not develop pelvic tactile allodynia at any time point. Although we observed no change in the levels of TRPV1 protein expression in the prostate from B6 mice with EAP, there was evidence of significant inflammation and elevated mast cell activation. Interestingly, the prostate from TRPV1 KO mice with EAP showed a lack of mast cell activation despite evidence of prostate inflammation. Next, we observed a significant increase of p-ERK1/2 in the DRG and spinal cord from B6 mice with EAP; however, p-ERK1/2 expression was unaltered in TRPV1 KO mice with EAP. Finally, we confirmed that intraurethral administration of a TRPV1 antagonist peptide reduced pelvic tactile allodynia in B6 mice with EAP after day 20. CONCLUSIONS: We demonstrated that in a murine model of CP/CPPS, the TRPV1 channel is key to persistent pelvic tactile allodynia and blocking TRPV1 in the prostate may be a promising strategy to quell chronic pelvic pain.

Effect of alcohol on chronic pelvic pain and prostatic inflammation in a mouse model of experimental autoimmune prostatitis.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent disease of the urogenital system. Alcohol has been reported to be closely related to CP/CPPS. Thus, we intended to verify the role of alcohol in CP/CPPS and determine the underlying mechanism. METHODS: We induced experimental autoimmune prostatitis (EAP) mouse model by intradermally injecting a mixture of prostate antigens (PAgs) and complete Freund's adjuvant on days 0 and 28. Mice were treated with alcohol (control-alcohol and EAP-alcohol groups) or vehicle (control-vehicle, and EAP-vehicle groups) from day 32 to 42. Forty-two days after PAg injection, the pathological appearance of the prostate tissues was evaluated, and histological analyses of the prostate were performed. Chronic pelvic pain was assessed by applying von Frey filaments to the lower abdomen. Proinflammatory cytokines were detected by enzyme-linked immunosorbent assay tests. Then, we explored the effects of the NLRP3 inhibitor MCC950 on chronic pelvic pain and prostatic inflammation in this model. RESULTS: Histological analyses showed diffuse inflammation in the stromal tissues that were characterized by severe infiltration of neutrophils and mononuclear cells in mice in the EAP-alcohol group compared with EAP-vehicle group. Chronic pain tests showed that the response frequency was significantly increased using a von Frey filament at forces of 0.4, 1.0, and 4.0 g in EAP-alcohol group compared with EAP-vehicle (P < .05). The levels of proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17, and IL-1ß were all significantly elevated in EAP-alcohol group compared with the EAP-vehicle group (P < .05). However, between the control-alcohol and control-vehicle groups, chronic pain tests, histological assays, and cytokine determinations showed no differences. Furthermore, our results demonstrated that MCC950 could decrease the expression level of NLRP3 inflammasome-related proteins including NLRP3, ASC, and caspase-1. The chronic pain tests, histological assays, and cytokine determinations showed that MCC950 could attenuate the chronic pain and prostatic inflammation through the inhibition of the NLRP3 inflammasome. CONCLUSIONS: This study indicated that alcohol could aggravate the severity of prostatic inflammation in EAP model though activating the NLRP3 inflammasome. Furthermore, the role of MCC950 in inhibiting NLRP3 inflammasome and decreasing IL-1ß secretion to alleviate EAP severity may show that it is a promising therapeutic agent for CP/CPPS.

Role of gram-positive bacteria in chronic pelvic pain syndrome (CPPS).

INTRODUCTION: Chronic pelvic pain syndrome (CPPS) is a complex disorder that affects a large proportion of all men. A limited understanding of its etiology and pathogenesis is reflected by the absence of effective therapies. Although CPPS is deemed clinically non-infectious with no well-defined etiological role for microbes, bacteria is readily isolated from both healthy and patient prostate secretion and urine samples. Our laboratory has previously demonstrated that a specific gram-negative bacterial isolate can induce CPPS-like symptoms in mice. Here we aimed to expand on these findings examining the role of gram-positive patient-derived bacteria in CPPS. METHODS: A retrospective analysis of bacterial cultures from CPPS patients from a single center was performed. Gram-positive bacteria were isolated from the expressed prostatic secretion (EPS) of three CPPS-patients (pain inducers, PI) and one from a healthy volunteer (non-pain inducer, NPI). These bacteria were inoculated intra-urethrally in two mouse backgrounds and analyzed for their ability to induce tactile allodynia, voiding dysfunction, and colonize the murine prostate. Host immune responses to bacterial instillation were analyzed by flow cytometry. RESULTS: PI strains (Staphylococcus haemolyticus 2551, Enterococcus faecalis 427, and Staphylococcus epidermidis 7244) induced and maintained tactile allodynia responses (200% increase above baseline) for 28 days in NOD/ShiLtJ mice. Conversely the healthy subject derived strain (Staphylococcus epidermidis NPI) demonstrated no significant pelvic allodynia induction. Intra-urethral inoculation of the four bacterial strains into C57BL/6 mice did not induce significant increases in pain responses. Infected NOD/ShiLtJ displayed significant voiding dysfunction compared to their control counterparts. Colony counts of prostate tissues from both NOD/ShiLtJ and C57BL/6 mice at day 28 demonstrated that bacterial strains colonized equally well, including NPI. We also determined that mechanistically, the patient-isolates induced prostate inflammation specifically involving T-cells and monocytes. CONCLUSIONS: Gram-positive isolates from CPPS patients showed enhanced ability to induce tactile allodynia compared to a single taxonomically similar gram-positive strain isolated from a healthy control. Responses were shown to be dependent on host genetic background and not on colonization differences between strains.

A nanoparticle-coupled T2 peptide induces immune tolerance and ameliorates chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in mice model.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex disease of unclear etiology. Precise treatment of CP/CPPS is not available due to lack of specific cause; however, autoimmunity is the most valid theory. We develop a new treatment strategy that involves synthesis and coupling of biodegradable nanoparticles to antigenic T2 peptide to induce immune tolerance in CP/CPPS mice models. A total of 50 male C57BL/6 mice were randomized into five groups, that is, naïve, Model, PLGA-PEMA, PLGA-PEMA-OVA323-339 , and PLGA-PEMA-T2 group. All groups except naïve were injected subcutaneously on day 0 with 0.2 mL of T2 peptide with CFA to generate valid CP/CPPS models. After successful induction of CP/CPPS, Model group, PLGA-PEMA, PLGA-PEMA-OVA, and PLGA-PEMA-T2 groups were treated with 0.15 mL of normal saline, 0.2 mg of PLGA-PEMA and PLG-PEMA-T2 and 0.3 mg PLGA-PEMA-OVA nanoparticles, respectively, on day 28. Hematoxylin and eosin staining, and ELISA were used to evaluate the variation in CP/CPPS manifestations and seral level of IL-10 in each group. Pain threshold and voiding behavior were also recorded for every group. Mice treated with PLGA-PEMA-T2 exhibited enhanced pain threshold, reduced urine frequency, and prostate pathology. Furthermore, serum level of inflammatory mediators (TNF-α and CRP) were reduced and anti-inflammatory IL-10 was enhanced in PLGA-PEMA-T2 group as compared to other groups. Our results demonstrate that PLGA-PEMA-T2 nanoparticle ameliorates disease manifestations in CP/CPPS mice models and upregulates IL-10 which is essential for tolerance induction. This strategy highlights the new therapeutic approach utilizing biodegradable nanoparticles for the treatment of CP/CPPS.

Crosstalk between the immune system and neural pathways in interstitial cystitis/bladder pain syndrome.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition causing intense pelvic pain and urinary symptoms. While it is thought to affect millions of people and significantly impair quality of life, difficulty with diagnosis and a lack of reliably effective treatment options leave much progress to be made in managing this condition. We describe what is currently known about the immunological and neurological basis of this disease, focusing on the interactions between the immune and nervous system. Evidence for immune involvement in IC/BPS comes from its high co-occurrence with known autoimmune diseases, altered cytokine profiles, and immune cell infiltration in patients. These cytokines have the ability to cross-talk with the nervous system via NGF signaling, resulting in hyper-sensitization of pain receptors, causing them to release substance P and creating a positive feedback loop of neuroinflammation. While it seems that the crosstalk between the immune and nervous system in IC is understood, much of the information comes from studying other diseases or from animal models, and it remains to be confirmed in patients with the disease. Identifying biomarkers and confirming the mechanism of IC/BPS are ultimately important for selecting drug targets and for improving the lives of patients with this disease.

Involvement of prostatic interstitial cells of Cajal in inflammatory cytokines-elicited catecholamines production: Implications for the pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

In a previous work using guinea pig prostate, we have identified a novel interstitial cells of Cajal (ICCs) which possess close contacts between sympathetic nerve bundles and smooth muscle cells. The ability of prostatic ICCs in mediating excitatory neural inputs was therefore studied using isolated murine prostate ICCs by collagenase digestion combined with FACS method. RT-PCR and Western blotting analyses revealed that prostatic ICCs under a quiescent state expressed abundantly the rate-limiting enzymes essential for catecholamine synthesis. Moreover, distinct proinflammatory cytokines (e.g. IL-1ß, IL-8, ICAM-1 and TNF-α) could significantly stimulate the expression levels of the rate-limiting enzymes of catecholamine production in prostate ICCs. Mechanistically, the above-mentioned stimulatory effects of proinflammatory cytokines appeared to be mediated via activation of NF-κB, HIF-1α and HDACs signaling pathways. Considering that prostatic catecholamine overactivity serves as an essential etiology of pelvic pain by indirectly stimulating the smooth muscle cell proliferation, or by directly causing muscular spasm, our results collectively suggest that targeting the NF-κB, HIF-1α and HDACs pathways in prostate ICCs be considered as a new strategy for treatment of chronic pelvic pain syndrome (CPPS) induced by chronic prostatitis (CP). Overall, the current study should shed novel light on the biology of this unique prostate ICCs.

Commensal bacterial modulation of the host immune response to ameliorate pain in a murine model of chronic prostatitis.

The human commensal microflora plays an essential role in modulating the immune response to control homeostasis. Staphylococcus epidermidis, a commensal bacterium most commonly associated with the skin exerts such effects locally, modulating local immune responses during inflammation and preventing superinfection by pathogens such as Staphylococcus aureus. Although the prostate is considered by many to be sterile, multiple investigations have shown that small numbers of gram-positive bacterial species such as S. epidermidis can be isolated from the expressed prostatic secretions of both healthy and diseased men. Chronic pelvic pain syndrome is a complex syndrome with symptoms including pain and lower urinary tract dysfunction. It has an unknown etiology and limited effective treatments but is associated with modulation of prostate immune responses. Chronic pelvic pain syndrome can be modeled using murine experimental prostatitis (EAP), where CD4+ve IL17A+ve T cells have been shown to play a critical role in disease orchestration and development of pelvic tactile allodynia. Here, we report that intraurethral instillation of a specific S. epidermidis strain (designated NPI [non-pain inducing]), isolated from the expressed prostatic secretion of a healthy human male, into EAP-treated mice reduced the pelvic tactile allodynia responses and increased CD4+ve IL17A+ve T-cell numbers associated with EAP. Furthermore, a cell wall constituent of NPI, lipoteichoic acid, specifically recapitulates these effects and mediates increased expression of CTLA4-like ligands PDL1 and PDL2 on prostatic CD11b+ve antigen-presenting cells. These results identify a new potential therapeutic role for commensal S. epidermidis NPI lipoteichoic acid in the treatment of prostatitis-associated pain.

A novel mouse model of chronic prostatitis/chronic pelvic pain syndrome induced by immunization of special peptide fragment with aluminum hydroxide adjuvant.

OBJECTIVES: CP/CPPS is a commonly observed distress in male patients. Because of its little-known etiology, no effective therapy has been developed which has promising outcomes. Therefore, there is a need to develop a valid model which can mimic the etiology of CP/CPPS. MATERIALS AND METHODS: Fifty male C57BL/6 mice were randomly and averagely divided into 5 groups of 10 mice each. The control group was injected with 0.9% NaCl solution. Aluminum hydroxide and T2 groups were injected with aluminum hydroxide adjuvant and T2 peptide. T2 plus complete Freund adjuvant (CFA) with aluminum hydroxide group was injected with a mixture of T2, CFA and aluminum hydroxide adjuvant. At the same time, CFA group was injected with complete Freund adjuvant. Hematoxylin-eosin stain and immunohistochemistry were used to investigate inflammatory lesion and expression of IL-ß1. Furthermore, TNF-α and CRP protein levels were evaluated by using commercially available ELISA kits. The ANOVA test was used to compare the statistical differences among groups. RESULTS: Prostates from a mixture of T2 plus CFA with aluminum hydroxide immunized mice showed elevated lesions and high level of inflammatory cells infiltration compared to the other groups. In addition, the levels of TNF-α, IL-ß1, and CRP were also higher in the T2 plus CFA with aluminum hydroxide group as compared to the other groups. CONCLUSION: Our results showed that T2 with CFA plus aluminum hydroxide adjuvant injection could successfully induce CP/CPPS in mice. This autoimmune novel model provides a useful, economic, safer, and easy tool for exploring the etiology and pathophysiology of CP/CPPS which will improve the therapeutic outcomes.

[Modern view on etiology, pathogenesis and treatment of chronic pelvic pain syndrome].

The manuscript presents the analysis of scientific manuscripts written by Russian and foreign researchers devoted to chronic pelvic pain syndrome (CPPS) studies. In spite of widespread disease, there is no clear understanding on etiopathogenetic mechanisms of CPPS development and it is shown that besides infectious process cardiovascular, neuronal, locomotor, endocrine and immune systems are involved into pathological process of CPPS. Mentioned factors complicate the doctors task on effective therapy choice and stress the reasonability of complex approach to CPPS treatment. Combination drug containing affinity purified antibodies to endothelial NO-synthase and prostate-specific antigen in released-active form influences different pathogenetic mechanisms of CPPS and thereby reveals pronounced clinical efficacy.

Chronic Infection of the Prostate by Chlamydia muridarum Is Accompanied by Local Inflammation and Pelvic Pain Development.

BACKGROUND: Chlamydia trachomatis urogenital infections are the leading cause of sexually transmitted bacterial infections. Although the prevalence of chlamydial infection is similar in men and women, current research is mainly focused on women, neglecting the study of male genital tract infections. We, therefore, investigated Chlamydia infection in the rodent male genital tract. MATERIALS AND METHODS: Male NOD and C57BL/6 mice were inoculated in the meatus urethra with C. muridarum. Bacterial DNA, leukocyte infiltration of male genital tract tissues, pelvic pain, and Chlamydia-specific immune responses were analyzed at different time points. RESULTS AND CONCLUSIONS: The inoculation of C. muridarum in the meatus urethra of male mice resulted in an ascending and widely disseminated infection of the male genital tract. C. muridarum remained longer and with the highest bacterial burdens in the prostate, thus showing a special tropism for this organ. Infection caused leukocyte infiltration, mainly composed by neutrophils, and also induced early pelvic pain development that rapidly dropped and resolved as the infection became chronic. Bacterial load and leukocyte infiltration was observed in all prostate lobes, although dorsolateral prostate was the most affected lobe. Interestingly, immune responses induced by both mice strains were characterized by the production of high levels of IL-10 during early stages of the infection, with highest and sustained levels observed in NOD mice, which showed to be less efficient in clearing the infection. Chronic infection of the prostate accompanied by local inflammation and pelvic pain development described herein have important implications for the improvement of the diagnosis and for the design of new efficient therapies. Prostate 77:517-529, 2017. © 2017 Wiley Periodicals, Inc.

Chronic Pelvic Pain Development and Prostate Inflammation in Strains of Mice With Different Susceptibility to Experimental Autoimmune Prostatitis.

BACKGROUND: Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of the prostate characterized by peripheral prostate-specific autoimmune responses associated with prostate inflammation. EAP is induced in rodents upon immunization with prostate antigens (PAg) plus adjuvants and shares important clinical and immunological features with the human disease chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: EAP was induced in young NOD, C57BL/6, and BALB/c male mice by immunization with PAg plus complete Freund́s adjuvant. Tactile allodynia was assessed using Von Frey fibers as a measure of pelvic pain at baseline and at different time points after immunization. Using conventional histology, immunohistochemistry, FACS analysis, and protein arrays, an interstrain comparative study of prostate cell infiltration and inflammation was performed. RESULTS: Chronic pelvic pain development was similar between immunized NOD and C57BL/6 mice, although the severity of leukocyte infiltration was greater in the first case. Coversely, minimal prostate cell infiltration was observed in immunized BALB/c mice, who showed no pelvic pain development. Increased numbers of mast cells, mostly degranulated, were detected in prostate samples from NOD and C57BL/6 mice, while lower total counts and resting were observed in BALB/c mice. Prostate tissue from NOD mice revealed markedly increased expression levels of inflammatory cytokines, chemokines, adhesion molecules, vascular endothelial growth factor, and metalloproteinases. Similar results, but to a lesser extent, were observed when analyzing prostate tissue from C57BL/6 mice. On the contrary, the expression of the above mediators was very low in prostate tissue from immunized BALB/c mice, showing significantly slight increments only for CXCL1 and IL4. CONCLUSIONS: Our results provide new evidence indicating that NOD, C57BL/6, and BALB/c mice develop different degrees of chronic pelvic pain, type, and amount of prostate cell infiltration and secretion of inflammatory mediators. Our results corroborate and support the notion that mice with different genetic background have different susceptibility to EAP induction. Prostate 77:94-104, 2017. © 2016 Wiley Periodicals, Inc.