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Identifying the mechanism of platelet activation by platelet factor 4 (PF4) a.k.a CXCL4

ABSTRACT: We discovered that platelets become activated by platelet factor 4 and have looked into how this is the case. We used phosphoproteomics to identify proteins that were phosphorylated in a band on a Western blot at 95 kDa and identified phospho STAT5. We have subsequently shown that PF4 activates platelets through the JAK/STAT pathway.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet

SUBMITTER: Richard Buka

LAB HEAD: Phillip L R Nicolson

PROVIDER: PXD043558 | Pride | 2024-06-16

REPOSITORIES: Pride

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			Action	DRS
	2022-07-29_RBuka_1Resting.mgf	Mgf
	2022-07-29_RBuka_1Resting.msf	Msf
	2022-07-29_RBuka_1Resting.mzML	Mzml
	2022-07-29_RBuka_1Resting.mzid.gz	Mzid
	2022-07-29_RBuka_1Resting.raw	Raw

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Publications

PF4 activates the c-Mpl-Jak2 pathway in platelets.

Buka Richard J RJ Montague Samantha J SJ Moran Luis A LA Martin Eleyna M EM Slater Alexandre A Watson Steve P SP Nicolson Phillip L R PLR

Blood 20240101 1

<h4>Abstract</h4>Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. Thi ...[more]

PMID: 37883794

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Project description:The goal of this experiment was to explore how human platelets affect the transcriptional responses of primary human CD14+ blood monocytes to lipopolysaccharide (LPS), and NLRP3 activation with Nigericin. For this purpose, we analyzed the mRNA expression of 770 myeloid-specific transcripts using the nCounter® Nanostring Human Myeloid Innate Immunity Panel v2. We isolated classical monocytes (CD14+CD16−) from the peripheral blood of healthy volunteers. Monocytes were derived from PBMCs using negative selection with the EasySep™ Human Monocyte Isolation Kit from STEMCELLTM Technologies. We modified this process by either including or excluding a platelet-depleting cocktail, creating two groups: \\"Standard Monocytes (StdMo)\\" and \\"Platelet-depleted Monocytes (PdMo).\\" To examine the impact of platelets further, we supplemented PdMos with fresh autologous platelets at a ratio of 50 platelets per monocyte, resulting in a third group, \\"PdMo + Plts.\\" StdMos were prepared according to the standard protocol provided by the EasySep™ Kit. For the PdMos, a Platelet Removal Component (50 µl ml−1) from the kit was used during isolation. We also reconstituted platelet-depleted monocytes with platelets and analyzed platelets alone to determine their specific mRNA contributions. The groups—StdMo, PdMo, PdMo + Plts, and platelets alone—were then exposed to 2 ng/ml of Ultrapure LPS (from E. coli O111:B4) for 4.5 hours, or stimulated with LPS for 3 hours followed by inflammasome activation with Nigericin (10 µM) for 90 min before extracting RNA for analysis.

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Platelet microRNA-mRNA Co-Expression Profiles Correlate with Platelet Reactivity

Project description:MicroRNAs (miRNAs) regulate cell physiology by altering protein expression, but the biology of platelet miRNAs is largely unexplored. We tested whether platelet miRNA levels were associated with platelet reactivity by genome-wide profiling using platelet RNA from 19 healthy subjects. We found that human platelets express 284 miRNAs. Unsupervised hierarchical clustering of miRNA profiles resulted in 2 groups of subjects that appeared to cluster by platelet aggregation phenotypes. Seventy-four miRNAs were differentially expressed (DE) between subjects grouped according to platelet aggregation to epinephrine, a subset of which predicted the platelet reactivity response. Using whole genome mRNA expression data on these same subjects, we computationally generated a high-priority list of miRNA-mRNA pairs in which the DE platelet miRNAs had binding sites in 3'UTRs of DE mRNAs, and the levels were negatively correlated. Three miRNA-mRNA pairs (miR-200b:PRKAR2B, miR-495:KLHL5 and miR-107:CLOCK) were selected from this list and all 3 miRNAs knocked down protein expression from the target mRNA. Reduced activation from platelets lacking PRKAR2B supported these findings. In summary, (1) platelet miRNAs are able to repress expression of platelet proteins, (2) miRNA profiles are associated with and may predict platelet reactivity, and (3) bioinformatic approaches can successfully identify functional miRNAs in platelets. Total RNA from the platelets of 19 donors was harvested and labeled with Hy3. Reference RNA (a pool of all samples) was labeled with Hy5. This submission represents the miRNA expression component of the study.

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High Field Asymmetric Waveform Ion Mobility Spectrometry in Non-targeted Bottom-up Proteomics of Dried Blood Spot

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