Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

Abstract

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells and the histamine 1 receptor in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.NEW AND NOTEWORTHYLUTS-associated BPH is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.

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

“…Once again, these findings mirror the human disease, since elevated levels of CCL2 and CCL3, the Th1-associated chemokine CXCL10, mast cellderived tryptase and other mediators, and significantly increased effector Th1/Th17 cell proportions have been found elevated in expressed prostatic secretions or peripheral blood from CPPS/CP patients, and correlating with pelvic pain symptoms (32, 66-71). Remarkably, recently reported data indicates that a mast celldirected therapy improved the quality of life of CPPS/CP patients by alleviating pain and urinary symptoms in association with a downregulation of immune-related pathways including Th1 and Th17 T cell differentiation (72). From all these evidence, IFNgsecreting Th1 lymphocytes emerge as central drivers in the pathogenesis of the disease and the development of chronic pelvic pain, the characteristic symptom observed in CPPS/CP patients.…”

mMCP7, a Mouse Ortholog of δ Tryptase, Mediates Pelvic Tactile Allodynia in a Model of Chronic Pelvic Pain

“…An important and noteworthy aspect is that in the EAP model of CP/CPPS, both NOD/ShiLtJ and C57BL/6 mice develop pelvic tactile allodynia, albeit the C57BL/6 mice develop pelvic tactile allodynia to a lesser extent ( 13 , 14 , 37 ). In both the EAP and the CP1-induced mouse models of prostatitis, we have shown increased numbers and activity of mast cells in the prostate stroma ( 13 , 14 , 29 , 39 ). Furthermore, in the EAP model, we have observed an increase in PGP9.5 +ve neuronal structures in the stroma of the prostates ( 37 , 50 ).…”

“…To assess the presence of mast cells, we examined prostate sections to determine the numbers of mast cells in both C57BL/6 and NOD/ShiLtJ mice upon CP1 instillation. We and others have previously demonstrated that following bacterial instillation, inflammation and mast cell numbers are most pronounced in the dorsolateral lobe of the prostate (29,39,40). Dorsolateral prostate lobe sections from CP1-infected mice and control C57BL/6 and NOD/ShiLtJ mice were subjected to toluidine blue staining to assess increase of mast cell numbers.…”