Acyloxyacyl hydrolase modulates pelvic pain severity

Abstract

Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2 progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.

AOAH remodels arachidonic acid-containing phospholipid pools in a model of interstitial cystitis pain: A MAPP Network study

“…Although lipidomics showed that sacral spinal cords of female wild type mice contained more AA-containing PE than AOAH-deficient mice, it was unclear whether AOAH could directly modulate the sequestration of AA among CNS phospholipids. Microarray analyses showed that variant 3 of human AOAH (hAOAH3) was highly expressed in the CNS compared to other hAOAH variants [ 5 , 11 , 26 ]. We generated a recombinant lentivirus encoding hAOAH3 and, after confirming that HEK293 cells lack AOAH expression by immunoblotting (not shown), transduced HEK293 cells with AOAH3 or lacZ to obtain the 293 lenti-hAOAH3 and 293 lenti-lacZ cells, respectively.…”

“…Previous research showed that administration of an EP1 antagonist alleviated rat cystitis and modulated pain [ 34 , 35 ]. To clarify the potential consequence of dysregulated AA homeostasis in the spontaneous pelvic pain phenotype of AOAH-deficient mice, we next examined the impact of EP1 antagonist ONO-8711 by quantifying pelvic mechanical allodynia in response to von Frey filaments applied to the pelvic region [ 5 ]. Briefly, 5 filaments of increasing stiffness (i.e., increasing applied force) were applied to the pelvic region ten times each and expresses at the percent responses to each stimulus force.…”

“…Finally, as reported here, we find AOAH-deficient mice exhibit evoked allodynia consistent with referred pelvic pain that is relieved by intrathecal administration of the EP1 antagonist ONO-8711 ( Fig 5 ). Aoah was originally identified as a modulator of pelvic pain in a genetic screen using a mast cell-dependent pain model [ 5 ], raising possible mast cell involvement. However, to date RNAseq data have not reported expression of Aoah mRNA in human mast cells, and we have not found the antihistamine ranitidine reduces allodynia of AOAH-deficient mice, despite effectively reducing allodynia in a mast cell-dependent model pain [ 54 , 55 ].…”

“…Because of the profound impact of chronic pelvic pain, the National Institute of Diabetes and Digestive and Kidney Diseases established the Multi-Disciplinary Approaches to Chronic Pelvic Pain Research Network, its flagship effort to understand mechanisms underlying urologic chronic pelvic pain syndromes [ 2 , 3 ]. As part of these studies, we recently employed a murine neurogenic cystitis model that recapitulates key aspects of IC [ 4 ] to identify loci that modulate pelvic pain using a quantitative trait loci genetic strategy, and we found that acyloxyacyl hydrolase (AOAH) is a novel modulator of pelvic pain [ 5 ]. AOAH-deficient mice were found to have spontaneously elevated mechanical allodynia of the pelvic region relative to wild type mice, an evoked behavioral response consistent with pelvic pain.…”

Disruption of female reproductive function by endotoxins

“…However, when LPS is transferred and bound to MD-2, the fatty acyl chains are less accessible, decreasing AOAH's ability to deacylate LPS and reduce TLR4 activation (Gioannini et al 2007). Whether the female reproductive tract has the capacity to locally detoxify LPS remains unknown though recently, the importance of AOAH in the lung (Zou et al 2017), urinary tract (Yang et al 2017) and colonic dendritic (Janelsins et al 2014) cells has been demonstrated.…”