IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP)

Murphy, SB; Schaeffer, Anthony J.; Done, Joseph D.; Wong, Larry; Bell-Cohn, Ashlee; Roman, Kenny; Cashy, John; Ohlhausen, Michelle; Thumbikat, Praveen

doi:10.1371/journal.pone.0125623

Cited by 45 publications

(54 citation statements)

References 62 publications

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“…The effect of NPI instillation on prostatic immune responses was examined by flow cytometric analysis of CD4+ve T-cells. Increased levels of CD4+ve IL17A+ve T-cells were observed upon induction of EAP in prostate tissues, (Figure 2c), as previously reported [25], and this increase was lost upon treatment with NPI for 7 days. We also observed a reversal of increased IL17A expressing CD4 T-cells in the iliac lymph nodes (Figure 2d) of EAP mice following NPI instillation, where levels returned to those similar to naïve mice.…”

Section: Resultssupporting

confidence: 86%

“…Increases in CD4+ve T-cell derived IL17A is necessary for initiation of pelvic tactile allodynia in the EAP murine model [32; 39]. Analysis of human EPS samples demonstrated that IL7, a cytokine involved in maintenance of activated CD4 T-cells [25], is increased in CPPS patients and correlated with pain severity. These lines of evidence suggest that the interplay between bacteria and the local immune system may have specific roles in determining referred alloydnia.…”

Section: Introductionmentioning

confidence: 99%

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

Murphy

Schaeffer²,

Done³

et al. 2017

Pain

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The human commensal microflora plays an essential role in modulating the immune response to control homeostasis. Staphylococcus epidermidis, a commensal bacteria 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. While 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 (EPS) of both healthy and diseased men. Chronic pelvic pain syndrome (CPPS) is a complex syndrome with symptoms including pain and lower urinary tract dysfunction (LUTs). It has an unknown etiology and limited effective treatments but is associated with modulation of prostate immune responses. CPPS 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 intra-urethral instillation of a specific S. epidermidis strain (designated NPI (non pain-inducing)), isolated from the EPS of a healthy human male, into EAP treated mice reduced the pelvic tactile allodynia responses and the increased CD4+ve IL17A+ve T-cell numbers associated with EAP. Furthermore, a cell wall constituent of NPI, lipotechoic acid (LTA), 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 LTA in the treatment of prostatitis-associated pain.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

Murphy

Schaeffer²,

Done³

et al. 2017

Pain

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“…Moseley and coworkers indicated that in current versions of the EST database some isoforms of IL-17 are expressed in the prostate [21]. Other authors also demonstrated by immunohistochemistry that IL-17 increases its expression in both stromal and epithelial tissue of the dorsolateral prostate in a murine prostatitis model [22]. In our case we observed in normal group an IL-17 signal in basal and luminal glandular regions (Figure 4(a)).…”

Section: Resultssupporting

confidence: 65%

Anti-Inflammatory Effect of Dialyzable Leukocyte Extract in Autoimmune Prostatitis: Evaluation in Animal Model

Pérez-Alvarado

Gómez

Reyes

et al. 2017

BioMed Research International

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Objective. To evaluate the anti-inflammatory properties of Dialyzable Leukocyte Extract (DLE) in a murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods. Histopathological characterization, prostatein Enzyme-Linked Immunosorbent Assay, and immunohistochemical analysis for CD45, TNF-α, IFN-γ, IL-6, IL-17, and IL-4 molecules were done in prostatic Wistar rats treated with DLE, placebo, or Dexamethasone. Results. Histopathological analysis of animals induced to prostatitis showed inflammatory infiltrate, mainly constituted by leucocytes and mast cells as well as Benign Prostatic Hyperplasia. Serum prostatein concentrations were 14 times higher than those displayed by healthy animals. After DLE and Dexamethasone treatments, the inflammatory infiltrate decreased; the tissue morphology was similar to that of a normal prostate, and the prostatein decreased to the basal levels of healthy animals. DLE treatment produced a decreased expression of the cell surface marker CD45 and the proinflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-17. On the other hand, the expression of anti-inflammatory cytokine IL-4 increased in both the Dexamethasone and DLE groups. Conclusion. DLE is able to modulate the inflammatory response in Experimental Autoimmune Prostatitis (EAP).

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“…Previous publications from our laboratory have demonstrated that EAP induced immune activation in prostate tissues is mediated by adaptive T-cell immune responses, specifically Th17 cells. 21 We hypothesized that PAR2 may mediate maintenance of inflammatory signals via mast cells and in doing so contribute to fibrosis. To address this we performed flow cytometry for a number of adaptive and innate immune cell markers at 5 and 30 days post-EAP induction in PAR2 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Role of PAR2 in the Development of Lower Urinary Tract Dysfunction

et al. 2016

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Purpose Lower urinary tract symptoms are a common finding in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We reported that the mast cell-tryptase-PAR2 axis plays a critical role in the development of chronic pain in experimental autoimmune prostatitis (EAP), a mouse model of CP/CPPS. We therefore examined whether PAR2 activation mediates lower urinary tract dysfunction. Materials and Methods Functional cystometry was used in male B6 mice along with immunoblots and immunohistochemistry for expression of collagen type I alpha I (COL1A1) and alpha-smooth muscle actin (α-SMA). Flow cytometric analysis was performed on single cell suspensions of the prostate, bladder, lymph nodes and spleen. Results and Conclusions EAP resulted in increased urinary voiding frequency and decreased bladder capacity thirty days after initiation. Concurrently there was increased expression of collagen type I alpha I (COL1A1) and alpha-smooth muscle actin (α-SMA) in the prostates and bladders. In contrast, induction of EAP in PAR2 KO mice did not result in altered urodynamics or increased markers of fibrosis in the prostate or the bladder. Single cell suspensions of the prostate, bladder, lymph nodes and spleen demonstrated that in the absence of PAR2, cellular inflammatory mechanisms were still initiated in EAP but PAR2 expression may be required for maintenance of chronic inflammation. Finally, we demonstrated that antibody mediated PAR2 neutralization normalized urinary voiding frequency and bladder capacity and attenuated chronic pelvic pain. PAR2 activation in the prostate may thus contribute to the development of lower urinary tract dysfunction through proinflammatory as well as profibrotic pathways.

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IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP)

Cited by 45 publications

References 62 publications

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

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

Anti-Inflammatory Effect of Dialyzable Leukocyte Extract in Autoimmune Prostatitis: Evaluation in Animal Model

Role of PAR2 in the Development of Lower Urinary Tract Dysfunction

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