Abstract
Chronic pelvic pain syndrome (CPPS) is the most common form of prostatitis, accounting for 90–95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP) in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17’s role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS.
Highlights
Symptomatic presentation of prostatitis accounts for 8% of all urologist visits and an estimated 1% of all primary care visits in the US and is categorized into five subsets
Experimental autoimmune prostatitis (EAP) is one such model where prostatitis and subsequent pelvic tactile allodynia is induced upon subcutaneous injection of rat prostate antigen behind the right shoulder of C57BL/6 mice
Intracellular staining for IFNγ revealed a similar trend that did not reach significance in either tissue, flow cytometry gating is depicted in S1 Fig Levels of CD4+ve CD25+ve FoxP3+ve cells appeared unchanged upon EAP induction
Summary
Symptomatic presentation of prostatitis accounts for 8% of all urologist visits and an estimated 1% of all primary care visits in the US and is categorized into five subsets. Experimental autoimmune prostatitis (EAP) is a non-infectious autoimmune driven murine model of CPPS and is induced by subcutaneous injection of rat prostate antigen and adjuvant into mice followed by weekly behavioral testing for development of pain Using this model our laboratory has previously shown that mast cells are crucial mediators of development of EAP induced pain in NOD mice [5] and that mast cell tryptase can mediate pain via the PAR2 receptor in C57BL/6 mice [6]. Studies using the uropathogenic E.coli (CP-1) infection murine model of CPPS have demonstrated an important role for Th17 T-cells in mediating prostatic autoimmunity and pelvic pain [3] This model differs significantly from the EAP model as induction of pain upon CP-1 infection only occurs in the genetically susceptible NOD background [7,8] and not in C57BL/6 mice. Multiple models of neuropathic pain have shown a role for IL17 in mediating pain and providing new avenues for development of therapeutics in chronic pain syndromes. [16,17,18]
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