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Dissecting the miR-451a-Mif Pathway in Endometriosis Pathophysiology Using a Syngeneic Mouse Model: Temporal Expression of Lesion Mif Receptors, Cd74 and Cxcr4

ABSTRACT: Endometriosis is an enigmatic disease characterized by pain and infertility in which endometrial tissue grows in ectopic locations, predominantly the pelvic cavity. The pathogenesis and pathophysiology of endometriosis is complex and postulated to involve alterations in inflammatory, cell proliferation and post-transcriptional regulatory pathways among others. Our understanding on the pathogenesis and pathophysiology of endometriosis is further complicated by the fact that endometriosis can only be diagnosed by laparoscopy only after the disease has manifested. This makes it difficult to understand the true pathogenesis as a cause-and-effect relationship is difficult to ascertain. To aid in our understanding on endometriosis pathogenesis and pathophysiology, numerous rodent models have been developed. In this case, we discuss further assessment of a miR-451a—macrophage migration inhibitory factor (Mif) pathway which contributes to lesion survival. Specifically, we evaluate the temporal expression of lesion Mif receptors, Cd74 and Cxcr4 using host mice which express wild-type or miR-451a deficient lesions. Similar to that observed in humans and a non-human primate model of endometriosis, Cd74 expression is elevated in lesion tissue in a temporal fashion while that of Cxcr4 shows minimal increase during initial lesion establishment but is reduced later during the lifespan. Absence of miR-451a during initial lesion establishment is associated with an augmentation of Cd74, but no Cxcr4 expression. The data obtained in this study provide further support for a role of Mif receptors, Cd74 and Cxcr4 in the pathophysiology of endometriosis.

SUBMITTER: Nothnick W

PROVIDER: S-EPMC9313350 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Although macrophage migration inhibitory factor ( MIF ) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD 74, the function of the soluble CD 74 receptor ectodomain ( sCD 74) and its interaction with circulating MIF have not been explored in cardiac disease. Methods and Results Cardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co-treatment with recombinant MIF and sCD 74 induced cell death ( P<0.001), which was mediated by receptor-interacting serine/threonine-protein kinase ( RIP) 1/ RIP 3-dependent necroptosis ( P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT - qPCR technology revealed a 4-fold upregulation of several interferon-induced genes upon co-treatment of myofibroblasts with sCD 74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD 74 as a modulator of MIF signaling by diminishing MIF -mediated protein kinase B ( AKT) activation ( P=0.0197) and triggering p38 activation ( P=0.0641). We obtained evidence that sCD 74 inhibits MIF -mediated survival pathway through the C-X-C chemokine receptor 4/ AKT axis, enabling the induction of CD 74-dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD 74/ MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244). Conclusions These findings suggest that treatment of cardiac myofibroblasts with sCD 74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD 74/ MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

Project description:BackgroundStrategies aimed at obtaining a complete cytoreduction are needed to improve long-term survival for patients with colorectal cancer peritoneal carcinomatosis (CRC-pc).MethodsWe established organoid models from peritoneal metastases of two naïve CRC patients. A standard paraffin inclusion was conducted to compare their 3D structure and immunohistochemical profile with that of the corresponding surgical samples. RNA expression levels of the CRC stem cell marker LGR5 was measured by in situ hybridization. The secretome of organoids was profiled by mass spectrometry. Energy homeostasis of organoids was interfered with 4-IPP and metformin. Biochemical and metabolic changes after drug treatments were investigated by western blot and mass spectrometry. Mitochondria impairment was evaluated by electron microscopy and mitotraker staining.ResultsThe two organoids recapitulated their corresponding clinical samples in terms of 3D structure and immmunoistochemical profile and were positive for the cancer stem cells marker LGR5. Proteomic analyses of organoids highlighted their strong dependence on energy producing pathways, which suggest that their targeting could be an effective therapeutic approach. To test this hypothesis, we treated organoids with two drugs that target metabolism acting on AMP-activated protein kinase (AMPK), the main regulator of cellular energy homeostasis, which may act as metabolic tumour suppressor in CRC. Organoids were treated with 4-IPP, an inhibitor of MIF/CD74 signalling axis which activates AMPK function, or metformin that inhibits mitochondrial respiratory chain complex I. As a new finding we observed that treatment with 4-IPP downregulated AMPK signalling activity, reduced AKT phosphorylation and activated a JNK-mediated stress-signalling response, thus generating mitochondrial impairment and cell death. Metformin treatment enhanced AMPK activation, decreasing the activity of the anabolic factors ribosomal protein S6 and p4EBP-1 and inducing mitochondrial depolarization.ConclusionWe provide evidence that the modulation of AMPK activity may be a strategy for targeting metabolism of CRC-pc organoids.

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Dissecting the miR-451a-Mif Pathway in Endometriosis Pathophysiology Using a Syngeneic Mouse Model: Temporal Expression of Lesion Mif Receptors, Cd74 and Cxcr4

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