Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome

Abstract

Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine experimental autoimmune prostatitis (EAP). Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia lead to ERK1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS.

Chronic Prostatitis Affects Male Reproductive Health and Is Associated with Systemic and Local Epigenetic Inactivation of C-X-C Motif Chemokine 12 Receptor C-X-C Chemokine Receptor Type 4

“…This corroborates other findings that mast cell signaling might be important in prostatitis [32,33,35] . Translating this finding into clinics, CP/CPPS patients with identified dysfunctions in the CXCL12 -CXCR4 -mast cell axis might benefit of agents regulating mast cell activity or CXCL12 / CXCR4 upstream pathways.…”

“…The involved molecular pathways in CP/CPPS patients are only partially understood. Animal and human models suggest a significant role of mast cells in the initiation of pain circuits and the chronification of the disease [32,33] . Further microarray analyses of inflammation in malign prostate tissue identified CXCL12 and its receptor CXCR4 as a major target gene involved in the recruitment of mast cells [25] .…”

Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation

“…Expressed prostatic secretions from men with CP/ CPPS had increased mast cell tryptase and nerve growth factor (NGF) levels . Mast cell infiltration and activation/degranulation has been shown to increase following induction of EAP 34,35,40 . Transgenic mice deficient in either mast cells 34 or the tryptase receptor PAR2 35 do not develop prostatic tactic sensitivity following EAP, unlike wildtype EAP mice.…”

“…Mast cell infiltration and activation/degranulation has been shown to increase following induction of EAP 34,35,40 . Transgenic mice deficient in either mast cells 34 or the tryptase receptor PAR2 35 do not develop prostatic tactic sensitivity following EAP, unlike wildtype EAP mice. While this preclinical model replicates many of the characteristics of human CP/CPPS, the induction protocol is not indicative of the human condition, which has a diverse etiology and often does not involve direct inflammation, infection, or injury of the prostate.…”

Kronik Prostatit/Kronik Pelvik Ağrı Sendromunda Etyoloji ve Tanı

“…İnflamasyona bağlı olarak ya da farklı nedenlerle kan spinal bariyerin bozulmasının spinal seviyedeki değişikliklerle ilgili olabileceği spinal seviyede mikroglia genişlemesinin bunun göstergesi olduğu kabul edilmektedir. CCL3, IL-1β, Iba1 ve ERK1/2 gibi maddelerin artmasının nöron aktivasyon eşiğini düşürdüğü, spinal seviyede P2X4R, BDNF artışı ve PAR2, cFos, Ca artışı olmasının moleküler düzeyde KPAS ile ilişkiyi açıklayabilecek nörot-ransmitterler olduğu kabul edilmektedir (57,58). Östradiol tarafından oluşturulan rat prostatit modelinde artan matriks metaloproteinazların (MMP-2 ve MMP-7'nin) lökosit infiltrasyonu, epitelyal atrofi ve doku hasarından sorumlu olabileceği bildirilmiştir (59).…”