Heme degradation pathway controls inflammation in model of mouse prostatitis
Abstract: Acute or chronic inflammation in the prostate is implicated in pathogenesis of benign prostate hyperplasia (BPH) as well as development of prostatic intraepithelial neoplasia (PIN) and prostate cancer (PCa). Chronic prostatitis (inflammation in the prostate) is associated with high morbidity and negatively impacts life quality. Macrophages are critical regulators of inflammatory processes and are early immune cells responders. Among macrophage-associated genes, the stress-induced enzyme heme oxygenase-1 (HO-1), which degrades heme to carbon monoxide (CO), biliverdin and iron, has strong immunomodulatory effects in in vitro and in vivo disease models. In this study, we investigated the specific role of HO-1 in macrophages on modulation of prostate inflammation. We established a mouse model of bacterial prostatitis in wild type mice, and evaluated the role of HO-1 in pathogen-induced prostate inflammation by using mice with conditional deletion of HO-1 in myeloid cells (LysM-Cre:Hmox1fl/fl). Immunohistological analysis showed increased infiltration of CD45 positive leukocytes and mitosis in the prostate glands as represented by phospho-Histone-H3 (p-HH3) staining in mice after bacterial challenge. Inflammation was accelerated in mice lacking myeloid-derived HO-1 with increased number of CD45 positive cells in the prostate glands. Further, we confirmed activation of the mitogen-activated protein kinase (MAPK) signaling pathway as observed by increased phosphorylation of extracellular signal-regulated kinase (Erk1/2) and induction of the inflammatory mediator interleukin-1β (IL-1β). Since exogenous CO mimics the majority, if not all, of the HO-1 effects, we asked whether CO plays a role in the model of prostatitis in mice. CO suppressed proliferation as shown by decreased p-HH3 staining and p-Erk1/2 levels in the inflamed mice prostates. CO also suppressed bacteria-induced expression of lipid metabolic enzymes acyl-CoA synthetase-1 (ACSL1) and fatty acid synthase (FAS), which mediated macrophage activation in other inflammation models. In summary, these results suggest that HO-1 plays a role in modulating pathogen-induced prostate inflammation via suppression of leukocyte influx and that exogenous CO may be used to block inflammation trigged proliferation and prevent PIN lesion formation.
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