The G‐protein‐coupled chemoattractant receptor Fpr2 exacerbates neuroglial dysfunction and angiogenesis in diabetic retinopathy

Yu, Ying; Xue, Shengding; Chen, Keqiang; Le, Yingying; Zhu, Rongrong; Wang, Shiyi; Liu, Shuang; Cheng, Xinliang; Guan, Huaijin; Wang, Ji Ming; Chen, Hui

doi:10.1096/fba.2020-00034

Cited by 5 publications

(13 citation statements)

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“…FPR2, a member of the formyl-peptide receptor family, is a G protein-coupled receptor (34). The physiological and pathological functions of FPR2 have been extensively studied using FPR2 agonists, RNA interference technology and FPR2 gene knockout mice, combined with in vitro and in vivo experiments.…”

Section: Discussionmentioning

confidence: 99%

FPR2 serves a role in recurrent spontaneous abortion by regulating trophoblast function via the PI3K/AKT signaling pathway

Zhang

et al. 2021

Mol Med Rep

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Recurrent spontaneous abortion (RSA) effects both the physical and mental health of women of reproductive age. Trophoblast dysfunction may result in RSA due to shallow placental implantation. The mechanisms underlying formyl peptide receptor 2 (FPR2) on the biological functions of trophoblasts remain to be elucidated. The present study aimed to explore the potential functions of FPR2, a G protein-coupled receptor, in placental trophoblasts. The location and expression levels of FPR2 in the villi tissue of patients with RSA were detected using immunohistochemical staining, reverse transcription-quantitative PCR and western blotting. Following the transfection of small interfering RNA targeting FPR2 in HTR-8/SVneo cells, a Cell Counting Kit-8 assay was used to determine the levels of cell viability. Flow cytometry was used to examine the levels of cell apoptosis and gap closure and Transwell assays were carried out to evaluate the levels of cell migration and invasion. A tube formation assay was performed to detect the levels of capillary-like structure formation. Western blotting was used to detect the expression levels of proteins in the associated signaling pathways. The expression of FPR2 was present in villi trophoblasts and was markedly increased in patients with RSA. The levels of trophoblast invasion, migration and tube formation were markedly increased following FPR2 knockdown, whereas the levels of apoptosis were markedly decreased. In addition, FPR2 knockdown caused an increase in the phosphorylation levels of AKT and PI3K. Thus, FPR2 may be involved in the regulation of trophoblast function via the PI3K/AKT signaling pathway. The results of the present study provided a theoretical basis for the use of FPR2 as a target for the treatment of trophoblast-associated diseases, such as RSA.

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Section: Discussionmentioning

confidence: 99%

FPR2 serves a role in recurrent spontaneous abortion by regulating trophoblast function via the PI3K/AKT signaling pathway

Zhang

et al. 2021

Mol Med Rep

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“…Fpr2 −/− mice were generated as described in our previous study, and C57BL/6 mice were used to establish a diabetic model [17]. Animal study was approved by the Institutional Animal Care and Use Committees in the Affiliated Hospital of Nantong University.…”

Section: Methodsmentioning

confidence: 99%

The G-Protein-Coupled Formyl Peptide Receptor 2 Promotes Endothelial-Mesenchymal Transition in Diabetic Retinopathy

et al. 2023

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Inrtoduction In proliferative diabetic retinopathy (PDR), retinal neovascularization is the essential pathogenic process that is linked to endothelial-to-mesenchymal transition (EndoMT) induced by high glucose (HG). This pathophysiological process may be regulated by a G-protein-coupled chemoattractant receptor FPR2 (mouse Fpr2), involved in inflammatory cell migration and proliferation. In the current study, we investigated the role of Fpr2 in regulating EndoMT and the underlying mechanisms during diabetic retinopathy progression. Methods FPR2 agonist or inhibitor was added to human microvascular endothelial cells (HMECs) exposed to normal glucose (NG) or HG. Morphologic, phenotypic, and functional changes of HMECs as well as the formation of microvasculature related to EndoMT were assessed. EndoMT biomarkers were detected in the retinal tissues of diabetic mice and fibrovascular epiretinal membranes (FVM) from patients with PDR. Results HG upregulated FPR2 in HMECs, which triggered morphological changes and the cells acquired mesenchymal phenotype, with enhanced cell migration, viability and angiogenic process shown by tube formation and aortic ring sprouting. Inhibition of FPR2 attenuated HG-induced EndoMT and endothelial cell migration to form vessel-like tube structures. RNA sequence and protein analysis further revealed that inhibition of FPR2 decreased the expression of genes associated with EndoMT. ERK 1/2 and P38 signaling pathway was activated in HMECs, promoting neovascularization in HG-induced EndoMT of HMECs. In vivo, increased expression of mesenchymal markers was detected in the retina of diabetic mice and FVMs from patients with PDR. FPR2 deficiency was associated with diminished EndoMT-related phenotypic changes in the retina of diabetic mice. Conclusions FPR2 is actively involved in the progression of EndoMT that may contribute to the pathogenesis of PDR. Thus, FPR2 may be a potential therapeutic target for PDR.

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“…These belong to the G-protein-coupled chemoattractant receptor family and are expressed by immune cells, including neutrophils, macrophages and microglia to mediate cell recruitment and release in response to pathogen-and tissue-derived chemotactic agonists. STZ administration results in an upregulation of formyl peptide receptors in mouse diabetic retinas, especially in retinal vascular endothelial cells, in association with an increased number of microglia [101].…”

Section: Streptozotocin (Stz)-induced Diabetic Micementioning

confidence: 96%

“…Other studies have induced diabetes in knockout (KO) mice to assess the specific role of the ablated protein in the inflammatory process. In this sense, formyl peptide receptors ablated (Fpr2 −/− ) mice treated with STZ have reduced activation of vascular endothelial cells and glia, with reduced production of pro-inflammatory cytokines [101]. In addition, diabetic lipocalin-2 KO mice show diminished STZ-induced Iba1 overexpression by microglia, limited macrophage infiltration and decreased proinflammatory cytokines expression including TNF-α and IL-6, supporting a role for lipocalin-2 in diabetes-induced brain inflammation [78].…”

Section: Streptozotocin (Stz)-induced Diabetic Micementioning

confidence: 99%

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

Vargas-Soria

García-Alloza

Corraliza-Gomez

2023

J Neuroinflammation

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Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.

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The G‐protein‐coupled chemoattractant receptor Fpr2 exacerbates neuroglial dysfunction and angiogenesis in diabetic retinopathy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 5 publications

References 50 publications

FPR2 serves a role in recurrent spontaneous abortion by regulating trophoblast function via the PI3K/AKT signaling pathway

FPR2 serves a role in recurrent spontaneous abortion by regulating trophoblast function via the PI3K/AKT signaling pathway

The G-Protein-Coupled Formyl Peptide Receptor 2 Promotes Endothelial-Mesenchymal Transition in Diabetic Retinopathy

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

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