NLRP3 inflammasome is involved in testicular inflammation induced by lipopolysaccharide in mice.

PROBLEM: Systemic inflammation induced by infection, which is associated with testicular inflammation, predisposes males to subfertility. Recently, the nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome was identified as a key mediator of inflammation, and excessive activation of the NLRP3 inflammasome was shown to contribute to the pathogenesis of a wide variety of diseases. However, the mechanisms underlying infectious inflammation in the testis remain unclear. We investigated the effect of lipopolysaccharide (LPS)-induced systemic inflammation on the role of the NLRP3 inflammasome in murine testes. METHOD OF STUDY: We performed in vivo and in vitro studies using an LPS-induced model of NLRP3 inflammasome activation and testicular inflammation. RESULTS: Intraperitoneal administration of LPS significantly impaired sperm motility in the epididymis of wild type (WT) and NLRP3-knockout (KO) mice. LPS administration stimulated interleukin (IL)-1ß production and secretion in the testes of WT mice, and these adverse effects were improved in the testes of NLRP3-KO mice. LPS administration also stimulated neutrophil infiltration as well as its chemoattractant C-C motif chemokine ligand 2 (CCL2) in WT testes, which were suppressed in NLRP3-KO testes. In in vitro cell culture, treatment with LPS and NLRP3 inflammasome activation significantly induced IL-1ß and CCL2 secretion from WT but not NLRP3-KO testicular cells. CONCLUSIONS: Taken together, our results suggest that testicular cells have the potential to secrete IL-1ß and CCL2 in an NLRP3 inflammasome-dependent manner and that these cytokines from the testis may further exacerbate testicular function, resulting in subfertility during infectious diseases.

Uncaria tomentosa extract (AC-11) improves pregnancy hypertension together with suppression of sFlt-1 and sEng.

Disruption of well-controlled reproductive functions leads to pregnancy complications such as hypertensive disorders of pregnancy (HDP). Uncaria tomentosa (Wild), known as cat's claw, is widely used for the treatment of a various types of health problems; AC-11 (AC-11®, hot-water extract of U. tomentosa) is unique phytochemical compound and has potential roles as anti-inflammatory or anti-oxidant processes. We investigated whether AC-11 has a protective effect on pathogenesis of HDP in vivo and production of anti-angiogenic factors (sFlt-1 and sEng, major factors for the onset of HDP) in in vitro. Non-pregnant or pregnant mice were administered AC-11 (4 mg/mL), then, angiotensin II (Ang II) was subcutaneously infused to increase blood pressure. Human placental tissues or human umbilical vein endothelial cells (HUVECs) were incubated with or without AC-11. Treatment with AC-11 significantly reduced blood pressure induced by Ang II infusion. The population of CD8+T cells, the ratio of CD8/CD4, and plasma interleukin-6 levels were increased by Ang II infusion, and were decreased by AC-11 both in pregnant and non-pregnant mice. In pregnant mice, plasma levels of sFlt-1 and sEng were decreased by AC-11. In in vitro cell culture of HUVECs or placental tissue culture, treatment with AC-11 significantly inhibited secretion of sFlt-1 and sEng. We suggest a novel role of AC-11 in regulating blood pressure by controlling the balance of T cell population and inflammatory cytokine production both in non-pregnant and pregnant conditions. In addition, AC-11 inhibits HDP-related factors, including sFlt-1 and sEng, suggesting that AC-11 may useful for relieving HDP.