Reduced inflammatory state promotes reinnervation of endometriotic-like lesions in TNFRp55 deficient mice

Abstract

Endometriosis is a chronic gynecological disease, characterized by growth of endometrial tissue in ectopic sites due to alteration of peritoneal homeostasis and deregulation of apoptosis. Here we have examined whether TNFRp55 deficiency modulates the pro-inflammatory state and the reinnervation of endometriotic-like lesions in mice. Two-month-old female C57BL/6 mice, eight wild type (WT) and eight TNFRp55−/− (KO) were used in the study. Endometriotic-like lesions were induced experimentally. The right uterine horn was removed from the animal, divided longitudinally, cut in three square pieces and sutured to the intestine mesentery. After 4 weeks, the lesions and the peritoneal fluid were collected. The level of TNFα in the peritoneal fluid was evaluated by enzyme-linked immunosorbent assay (EIA). The expressions of COX2, GRα and GRβ were evaluated in the lesions by western blot and immunohistochemistry. β-III TUBULIN, BDNF and NGF protein concentrations were evaluated in the lesions by western blot. Gene expression of Pgp 9.5, SP and Th was analyzed by RT-PCR, whereas relative concentrations of TRKA, NTRp75, phosphorylated NFκB (pNFκB) and total NFκB in lesions were measured by EIA. Compared with the WT group, the KO mice showed lower TNFα levels in the peritoneal fluid and lower numbers of COX2 immunoreactive cells along with increased expression of GRα, β-III TUBULIN, Pgp 9.5, SP, Th, BDNF, NGF, NTRp75 and pNFκB in the lesions. Future histological studies will be necessary to confirm the sensory/sympathetic imbalance in the endometriotic-like lesions of the KO mice. Our results suggest that a reduced inflammatory state promotes reinnervation of endometriotic-like lesions in TNFRp55−/− mice. Chronic deregulation of TNF receptors can have serious consequences for women with advanced endometriosis.

Copper in Gynecological Diseases

“…We found that the surgical establishment of EDT in mice increased the concentrations of Cu and estradiol, and the administration of a Cu chelating drug decreased both concentrations to values similar to the group with placebo surgery [208]. We also found similar results in another study [209], in which elevated Cu and estradiol levels were efficiently reduced by a Cu chelator in a murine model deficient in tumor necrosis factor (TNF-α) receptor 1 (TNFR1), which presents an aggravated state of EDT [202,210,211].…”

The copper chelator ammonium tetrathiomolybdate inhibits the progression of experimental endometriosis in TNFR1-deficient mice

“…It is important to mention that, in the absence of TNFR1, all TNFR2-dependent pathways become relevant, particularly those related to cell proliferation, survival, and angiogenesis 8 . In fact, in a previous study carried out in TNFR1 −/− animals, it was found that there was greater activation of NF-κB than in wild-type animals 14 . Therefore, we postulate that, in the absence of TNFR1, there is not only an interruption of the recognized crosstalk between both TNFRs 10 but also an alteration of TNFR2 signaling by TM.…”

“…In contrast, the TNFR2 levels and TNF-α increased as EDT worsened 13 . We previously showed that, in TNFR1-deficient mice, a worsening of pathology is observed compared to the EDT progression in wild-type mice 5 , 6 , 14 .…”

Unveil the pain of endometriosis: from the perspective of the nervous system

“…The increase in neurotrophic factors may be responsible for stimulating nerve development and boosting the growth of sensory nerves (Ref. 29). Further research into the specific mechanisms, NGFs in rats' ovaries were found to affect the expression of neurotransmitter-related enzymes in noradrenergic and cholinergic systems, causing the corresponding neurotransmitter content to change and subsequent cascade response (Ref.…”