Dataset Information

Quantitative phosphoproteomics reveals diverse stimuli activate distinct signaling pathways during neutrophil activation

ABSTRACT: Neutrophils play an active role in acute and chronic inflammation by exhibiting functional heterogeneity. Besides beneficial role in acute infections to eliminate pathogens, neutrophils also contribute to pathogenesis of diseases associated with sterile inflammation including vascular disorders, autoimmune diseases, Type 2 diabetes (T2D) and cancers. During T2D, hyperglycemia constitutively activate neutrophils. In the context of T2D associated complications, we examined influence of high glucose, homocysteine and LPS representing effector molecules of hyperglycemia, thrombosis, and infection respectively on human neutrophil activation to identify distinct signaling pathways by quantitative phosphoproteomics approach.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil, Blood

SUBMITTER: Keshava Prasad T. S.

LAB HEAD: T. S. Keshava Prasad

PROVIDER: PXD029046 | Pride | 2022-08-11

REPOSITORIES: Pride

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Publications

Quantitative phosphoproteomics reveals diverse stimuli activate distinct signaling pathways during neutrophil activation.

Thimmappa Pooja Yedehalli PY Nair Aswathy S AS Najar Mohd Altaf MA Mohanty Varshasnatha V Shastry Shamee S Prasad Thottethodi Subrahmanya Keshava TSK Joshi Manjunath B MB

Cell and tissue research 20220527 2

Neutrophils display functional heterogeneity upon responding diversely to physiological and pathological stimulations. During type 2 diabetes (T2D), hyperglycemia constitutively activates neutrophils, leading to reduced response to infections and on the other hand, elevated metabolic intermediates such as homocysteine induce bidirectional activation of platelets and neutrophils leading to thrombosis. Hence, in the context of T2D-associated complications, we examined the influence of high glucose ...[more]

PMID: 35622142

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Project description:Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients. Results: Microarray analysis identified 282 genes differing in expression between newlydiagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of interleukin-1Î² (IL1B), early growth response gene 3 (EGR3), and prostaglandin-endoperoxide; synthase 2 (PTGS2) resolved within four months of insulin therapy and were also observed in T2D suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81/282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly-connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D. Conclusion: T1D and T2D likely share a final common pathway for beta cell dysfunction that includes secretion of interleukin-1Î² and prostaglandins by immune effector cells, exacerbating existing beta cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy. Experiment Overall Design: We obtained blood samples from 24 healthy volunteers, 43 newly diagnosed T1D patients and 12 newly diagnosed T2D patients. All study participants were between the ages of 2 and 18 years. We collected samples one and four months after diagnosis from the last 20 of the T1D patients. For each time point one sample did not pass quality control and was dropped from the analysis. Patients with T2D were distinguished from T1D on the basis of age, body habitus, Experiment Overall Design: presence (11/12 patients) of acanthosis nigricans, family history of type 2 diabetes (11/12 patients), and absence of autoantibodies to insulin, IA-2, and GAD65. We allowed low titers of insulin antibodies in T2D patients (< 4 U/mL), which have been previously reported. All but two Experiment Overall Design: of the T1D patients with positive anti-insulin antibodies were also positive for at least one additional autoantibody.

Dataset Information

Quantitative phosphoproteomics reveals diverse stimuli activate distinct signaling pathways during neutrophil activation

Publications

Quantitative phosphoproteomics reveals diverse stimuli activate distinct signaling pathways during neutrophil activation.

Similar Datasets

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