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The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation.

ABSTRACT: NLRP3 plays a role in vascular diseases. Corpora cavernosa (CC) is an extension of the vasculature. We hypothesize that NLRP3 plays a deleterious role in CC relaxation. Male C57BL/6 (WT) and NLRP3 deficient (NLRP3^-/-) mice were used. Intracavernosal pressure (ICP/MAP) measurement was performed. Functional responses were obtained from CC strips of WT and NLRP3^-/- mice before and after MCC950 (NLRP3 inhibitor) or LPS?+?ATP (NLRP3 stimulation). NLRP3, caspase-1, IL-1?, eNOS, nNOS, guanylyl cyclase-?1 (GC?1) and PKG1 protein expressions were determined. ICP/MAP and sodium nitroprusside (SNP)-induced relaxation in CC were decreased in NLRP3^-/- mice. Caspase-1, IL-1? and eNOS activity were increased, but PKG1 was reduced in CC of NLRP3^-/-. MCC950 decreased non-adrenergic non-cholinergic (NANC), acetylcholine (ACh), and SNP-induced relaxation in WT mice. MCC950 did not alter NLRP3, caspase-1 and IL-1?, but reduced GC?1 expression. Although LPS?+?ATP decreased ACh- and SNP-, it increased NANC-induced relaxation in CC from WT, but not from NLRP3^-/- mice. LPS?+?ATP increased NLRP3, caspase-1 and interleukin-1? (IL-1?). Conversely, it reduced eNOS activity and GC?1 expression. NLRP3 plays a dual role in CC relaxation, with its inhibition leading to impairment of nitric oxide-mediated relaxation, while its activation by LPS?+?ATP causes decreased CC sensitivity to NO and endothelium-dependent relaxation.

SUBMITTER: Fais RS

PROVIDER: S-EPMC6838322 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation.

Fais Rafael S RS Rodrigues Fernanda L FL Pereira Camila A CA Mendes Allan C AC Mestriner Fabíola F Tostes Rita C RC Carneiro Fernando S FS

Scientific reports 20191107 1

NLRP3 plays a role in vascular diseases. Corpora cavernosa (CC) is an extension of the vasculature. We hypothesize that NLRP3 plays a deleterious role in CC relaxation. Male C57BL/6 (WT) and NLRP3 deficient (NLRP3<sup>-/-</sup>) mice were used. Intracavernosal pressure (ICP/MAP) measurement was performed. Functional responses were obtained from CC strips of WT and NLRP3<sup>-/-</sup> mice before and after MCC950 (NLRP3 inhibitor) or LPS + ATP (NLRP3 stimulation). NLRP3, caspase-1, IL-1β, eNOS, n ...[more]

PMID: 31700106

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Project description:Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice. We show that in vitro Toxoplasma infection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1? (IL-1?), with no measurable cleavage of IL-18 and no pyroptosis. Paradoxically, Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1? in their serum. Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death. Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality. Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival. Our findings reveal T. gondii as a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis.Inflammasomes are multiprotein complexes that are a major component of the innate immune system. They contain "sensor" proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1? (IL-1?) and IL-18. Toxoplasma gondii is a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance. We report here that T. gondii is a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival.

Project description:INTRODUCTION:Prosthesis-assisted penile reconstruction has been performed extensively to restore a cosmetically acceptable phallus. However, a large number of patients will undergo revision surgery for various prosthesis-related complications. AIM:To develop a 1-stage prosthesis-free dynamic cavernosa reconstruction method using bilateral innervated gracilis muscles and to investigate the feasibility and reliability of the surgical design. METHODS:10 fresh cadavers were dissected to assess the availability of bilateral gracilis muscles for functional cavernosa rebuilding. 11 mongrel female dogs were involved in the penile reconstruction surgery. The neophallus consisted of bilateral gracilis muscles as the neo-cavernosa, a right gracilis skin flap as the neourethra, and a lower abdominal flap with an anterior rectus sheath as the skin envelope and neo-tunica albuginea. The function and structure of the neo-phalli were assessed 7 months postoperatively. MAIN OUTCOME MEASURES:The neurovascular pedicle length of the gracilis muscles and the volume of the gracilis venter musculi were measured in the cadaveric investigation. The average dimensions of the canine neo-phalli at rest and during electrostimulated erection were obtained and the muscular fatigue-resistant curve was drawn. Histologic evaluations also were performed. RESULTS:The neurovascular pedicle length and volume of the gracilis muscles were sufficient to yield a nearly normal appearance of the neo-cavernosa in the cadaveric and animal studies. The muscular fatigue-resistant curve demonstrated adequate length, stiffness, and duration of erection of the neo-phalli to accomplish normal coitus. Histologic evaluations showed an intact neourethra and nearly normal muscle structure in the inner layer of the canine neo-cavernosa, except for significantly increased amount of collagen fibers and type I/III collagen ratio in the outer layer of the neo-cavernosa. The percentage of type II (fatigue-prone) muscle fibers did not change significantly. CONCLUSION:Our preclinical investigation proves that corpora cavernosa reconstruction using bilateral innervated gracilis muscles is technically feasible and functionally efficacious. Yin Z, Liu L, Xue B, et al. Dynamic Penile Corpora Cavernosa Reconstruction Using Bilateral Innervated Gracilis Muscles: A Preclinical Investigation. Sex Med 2018;6:162-170.

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The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation.

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The inflammasome NLRP3 plays a dual role on mouse corpora cavernosa relaxation.

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