Dysregulation of Cell Death and Its Epigenetic Mechanisms in Systemic Lupus Erythematosus

Wu, Haijing; Fu, Siqi; Zhao, Ming; Lü, Lei; Lu, Qianjin

doi:10.3390/molecules22010030

Cited by 33 publications

(26 citation statements)

References 94 publications

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“…Accumulated ACs are a contributing factor for the exposure of autoantigens to the immune system that eventually leads to autoimmunity like SLE [1,18]. Herein we showed that ACs could be engulfed by UC MSCs and these MSCs exhibited enhanced immunosuppressive function through the activation release of PGE2, which involved NF-κB signalling pathway.…”

Section: Discussionmentioning

confidence: 85%

Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2

Zhang

Huang

et al. 2019

EBioMedicine

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Background Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown. Methods Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium (ACMCM), and then CD4 + T cell proliferation was detected. Soluble factors including prostaglandin (PG)E2 in the supernatants of MSCs and AC-MSCs, as well as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX)2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively. Findings Human UC MSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4 + T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-κB signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation. Interpretation Clearance of ACs by MSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy. Fund This study was supported by grants from the Chinese Major International (Regional) Joint Research Project (No. 81720108020), the Jiangsu Province Major Research and Development Program (No. BE2015602) and the Jiangsu Province 333 Talent Grant (BRA2016001). WJ. Chen was supported by the Intramural Research Program of NIH, NIDCR.

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Section: Discussionmentioning

confidence: 85%

Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2

Zhang

Huang

et al. 2019

EBioMedicine

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“…This process plays an integral role in biological functions as diverse as tissue turnover [3], adaptive immunity [4], angiogenesis [5], and normal wound healing [6,7]. Subtle alterations in apoptosis susceptibility of a particular cell population can be a necessary part of homeostasis or can contribute to disease pathogenesis [8–12]. For these reasons, apoptosis is a far-reaching and popular subject of interest in many biological research laboratories.…”

Section: Introductionmentioning

confidence: 99%

An accessible and high-throughput strategy of continuously monitoring apoptosis by fluorescent detection of caspase activation

Finkelstein

2019

Analytical Biochemistry

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We present a real-time, high-throughput, and cost-effective method of detecting apoptosis in vitro using a previously developed reagent that detects caspase activation by fluorescence. Current methods of assessing apoptosis fail to account for the dimension of time, and thus are limited in data yielded per sample. This reagent allows real-time detection of apoptosis, but until now has been restricted to a costly automated detection system. Here, we describe apoptosis detection with the Essen Bioscience IncuCyte® Caspase-3/7 Reagent using a multimode microplate reader, a common instrument in biological laboratories, which may be used prior to or in lieu of the automated system. This modified microplate reader apoptosis assay was validated against the established automated system, and was shown to detect a strong dose-response relationship (automated system r2 = 0.9968, microplate reader r2 = 0.9924). We also propose a quick and reliable method of quantifying cell density by Hoechst 33342 nuclear staining in microplates (r2 = 0.8812 between Hoechst signal and cell density). We assert that the dimension of time should not be overlooked, and that the method presented here is an accessible strategy for many researchers due to low startup cost and precise detection of apoptosis in real time.

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“…Although microparticles have been described in systemic lupus erythematous [17,18], they appear to be unrelated to the microcomplexes described herein because they are too large (0.1-1.0 μm) to pass through 10 kDa cut-off ultrafilters.…”

Section: Discussionmentioning

confidence: 81%

The role of free endosomal epitopes in the mechanisms of amelioration and flares of rheumatoid arthritis-associated conditions: pregnancy and infective hepatitis

Caruso

Caruso²,

Santandrea

et al. 2018

transl med commun

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Background: It is known that rheumatoid symptoms improve in pregnancy and in patients who develop infective jaundice. The mechanism of amelioration might involve the direct interaction of free endosomal self-epitopes that are released by the cells of the involved organ with antigen binding sites on the membranes of anti-idiotypic cells, resulting in possible suppressive effects. Methods: Immune responses of peripheral blood mononuclear cells (PBMCs) to longstanding synovial fluid (SFMC or primary ultrafiltrate) and to the endosomal extracts enriched with self-epitope-receptor microcomplexes (MICs) were investigated. The MICs (secondary ultrafiltrate) were prepared from PBMCs that were previously cultured with SFMC ultrafiltrates and had therefore been in contact with large number of self-epitopes.Results: Addition of primary ultrafiltrate to PBMCs elicited significant expansion of regulatory T cells (CTLA-4+CD4 +CD25+), and reduction of CD69+CD4+CD25+ cells. In contrast, secondary ultrafiltrate, which contains the microcomplexes, produced an inflammatory response, with CD69+ cells increasing to 47% of CD4+CD25+ cells. This opposite response indicated that, in all likelihood, the response of mononuclear cells to secondary ultrafiltrate in culture involved a subset of CD4+ T cells other than those of the primary ultrafiltrate. Conclusions: Free endosomal epitopes, released from the maternal-fetal interface and necrotic areas of diseased liver, inducing expansion of regulatory T cells, provided a type of endogenous, autonomic immunotherapy. The post-partum flare-up of the disease could be due to the sudden interruption of endogenous immunotherapy at delivery and to the inflammatory response to microcomplexes that are recognized by autoreactive T cells.

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Dysregulation of Cell Death and Its Epigenetic Mechanisms in Systemic Lupus Erythematosus

Cited by 33 publications

References 94 publications

Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2

Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2

An accessible and high-throughput strategy of continuously monitoring apoptosis by fluorescent detection of caspase activation

The role of free endosomal epitopes in the mechanisms of amelioration and flares of rheumatoid arthritis-associated conditions: pregnancy and infective hepatitis

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