P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis

Albayati, Samara; Vemulapalli, Harika; Tsygankov, Alexander Y.

doi:10.1002/jlb.3a0220-097r

Cited by 15 publications

(24 citation statements)

References 46 publications

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“…Leukocytes play a fundamental role in innate and adaptive immunity, wound healing, tumor surveillance, and tissue remodeling. Platelets therefore circulate in a quiescent state and were rapidly activated by invading pathogens and other stimuli [ 31 ]. Measurement of miRNAs (127 and 320a) revealed this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Detection of Sepsis in Platelets Using MicroRNAs and Membrane Antigens

Corrêa

Carneiro²,

Valente

et al. 2021

Genes

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The present study proposes to legitimize in sepsis a characteristic found in platelets that suffer storage lesions in blood banks, which is the increased expression of miRNA miR-320a in relation to miR-127. Under physiologically normal conditions, an inverse relationship is observed. The aim of this study was to verify whether the analysis of miR-320a and miR-127 expression in platelets could detect a decrease in their viability and function due to the presence of pathogens in the blood of patients hospitalized in the Intensive Care Unit. We also investigated the expression of membrane antigens sensitive to platelet activation. Of the 200 patients analyzed, only those who developed sepsis (140) were found to have a higher relative quantity of miR-320a than that of miR-127. This characteristic and the increased expression of membrane antigens P2Y12, CD62P, CD41, and CD61 showed a significant association (p < 0.01) with all types of sepsis evaluated in this study. Additionally, 40% of patients hospitalized for sepsis had negative results for the first cultures. We conclude that analysis of miR-127 and miR-320a expression combined with membrane antigens evaluation, in association with the available clinical and diagnostic parameters, are important tools to detect the onset of sepsis.

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Section: Discussionmentioning

confidence: 99%

Detection of Sepsis in Platelets Using MicroRNAs and Membrane Antigens

Corrêa

Carneiro²,

Valente

et al. 2021

Genes

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“…The cecal ligation and double puncture (CLP) procedures were performed on under anesthesia with isoflurane (2 ± 4% induction in chamber and 1 ± 2% maintenance in mask) as described previously ( 26 , 31 – 33 ). Following midline laparotomy, the cecum was identified, the mesentery trimmed, and the stalk joining the cecum to the large intestine ligated.…”

Section: Methodsmentioning

confidence: 99%

Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis

Amoafo

Entsie²,

Albayati³

et al. 2022

Front. Immunol.

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Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high mortality. Sex-related differences in the immune response to sepsis have been proposed but the mechanism is still unknown. Purinergic signaling is a sex-specific regulatory mechanism in immune cell physiology. Our studies have shown that blocking the ADP-receptor P2Y12 but not P2Y1 receptor was protective in male mice during sepsis, but not female. We now hypothesize that there are sex-related differences in modulating P2Y12 or P2Y1 signaling pathways during sepsis. Male and female wild-type (WT), P2Y12 knock-out (KO), and P2Y1 KO mice underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. The P2Y12 antagonist ticagrelor or the P2Y1 antagonist MRS2279 were administered intra-peritoneally after surgery to septic male and female mice. Blood, lungs and kidneys were collected 24 hours post-surgery. Sepsis-induced changes in platelet activation, secretion and platelet interaction with immune cells were measured by flow cytometry. Neutrophil infiltration in the lung and kidney was determined by a myeloperoxidase (MPO) colorimetric assay kit. Sepsis-induced platelet activation, secretion and aggregate formation were reduced in male CLP P2Y12 KO and in female CLP P2Y1 KO mice compared with their CLP WT counterpart. Sepsis-induced MPO activity was reduced in male CLP P2Y12 KO and CLP P2Y1 KO female mice. CLP males treated with ticagrelor or MRS2279 showed a decrease in sepsis-induced MPO levels in lung and kidneys, aggregate formation, and platelet activation as compared to untreated male CLP mice. There were no differences in platelet activation, aggregate formation, and neutrophil infiltration in lung and kidney between female CLP mice and female CLP mice treated with ticagrelor or MRS2279. In human T lymphocytes, blocking P2Y1 or P2Y12 alters cell growth and secretion in vitro in a sex-dependent manner, supporting the data obtained in mice. In conclusion, targeting purinergic signaling represents a promising therapy for sepsis but drug targeting purinergic signaling is sex-specific and needs to be investigated to determine sex-related targeted therapies in sepsis.

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“…They act on both the innate and adaptive immune systems, dampening immune functions, causing immuno-paralysis, and eventually leading to MODS and death in sepsis (14,18,(122)(123)(124)(125). Intervention strategies (Tables 3 and 4), such as human recombinant cytokines (IL-15 and IL-36) (59,101), blocking phenotypes or chemokines [neuropilin (Nrp)-1, CTLA-4, lymphocyte activation gene (LAG)-3, and chemokine (C-X-C motif) ligand (CXCL) 4)] (50,58,77,82), nutrients (glutamine) (107), inhibiting molecules [sema3A, tissuenonspecific alkaline phosphatase (TNAP), Sirtuin1, P2Y12, COX-2, and poly ADP-ribose polymerase (PARP)] (48,51,102,(111)(112)(113), as well as even clinical therapeutics (high-volume hemofiltration, immunoglobulin, fresh frozen plasma, stem cells, and ulinastatin) (41,114,115,117,118) and traditional Chinese medicine (TCM) (electroacupuncture and tanshinone IIA) (103,106), can increase the chance of survival by inhibiting the heterogeneous characteristics of Treg-induced immunosuppression. Alternatively, other studies have shown improved outcomes in sepsis by increasing the heterogeneous characteristics of Tregs to inhibit sepsis-induced SIRS through intervention strategies such as human recombinant cytokines (IL-38 and IL-7) (96,97), blocking phenotypes or cytokines (CD28 and IL-3) (81,95), nutrients (arginine and fiber cellulose) (108,109), and others (bilirubin, ITK inhibitor, miR-126, maresin1, excretory-secretory products of Trichinella spiralis adult worms, and adipose-derived mesenchymal stem cell-derived exosomes) (19,…”

Section: Treg Heterogeneity In Sepsismentioning

confidence: 99%

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

et al. 2022

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Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.

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P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis

Cited by 15 publications

References 46 publications

Detection of Sepsis in Platelets Using MicroRNAs and Membrane Antigens

Detection of Sepsis in Platelets Using MicroRNAs and Membrane Antigens

Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

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