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Blood-Borne Microparticles Are an Inflammatory Stimulus in Type 2 Diabetes Mellitus
Stephen R Thom1, Veena M Bhopale1, Awadhesh K Arya1
1Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD.
Abstract:
The proinflammatory state associated with diabetes mellitus (DM) remains poorly understood. We found patients with DM have 3- to 14-fold elevations of blood-borne microparticles (MPs) that bind phalloidin (Ph; Ph positive [+] MPs), indicating the presence of F-actin on their surface. We hypothesized that F-actin-coated MPs were an unrecognized cause for DM-associated proinflammatory status. Ph+MPs, but not Ph-negative MPs, activate human and murine (Mus musculus) neutrophils through biophysical attributes of F-actin and membrane expression of phosphatidylserine (PS). Neutrophils respond to Ph+MPs via a linked membrane array, including the receptor for advanced glycation end products and CD36, PS-binding membrane receptors. These proteins in conjunction with TLR4 are coupled to NO synthase 1 adaptor protein (NOS1AP). Neutrophil activation occurs because of Ph+MPs causing elevations of NF-κB and Src kinase (SrcK) via a concurrent increased association of NO synthase 2 and SrcK with NOS1AP, resulting in SrcK S-nitrosylation. We conclude that NOS1AP links PS-binding receptors with intracellular regulatory proteins. Ph+MPs are alarmins present in normal human plasma and are increased in those with DM and especially those with DM and a lower-extremity ulcer.
Insights
Elevated microparticles coated with F-actin (Ph+MPs) are found in diabetes mellitus (DM) patients. These Ph+MPs activate neutrophils, contributing to the proinflammatory state seen in DM, particularly in those with ulcers.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- The proinflammatory state in diabetes mellitus (DM) is not fully understood.
- Blood-borne microparticles (MPs) are implicated in various disease states.
Purpose of the Study:
- To investigate the role of F-actin-coated microparticles (Ph+MPs) in the proinflammatory status of DM.
- To identify the mechanisms by which Ph+MPs activate neutrophils.
Main Methods:
- Quantification of Ph+MPs in patients with and without DM.
- In vitro activation assays of human and murine neutrophils using Ph+MPs.
- Analysis of neutrophil signaling pathways, including NF-κB, Src kinase, and TLR4.
Main Results:
- Patients with DM exhibit 3- to 14-fold elevations in Ph+MPs compared to healthy individuals.
- Ph+MPs, but not Ph-negative MPs, activate neutrophils via F-actin and phosphatidylserine (PS) expression.
- Neutrophil activation involves advanced glycation end products receptor, CD36, TLR4, and NOS1AP, leading to SrcK S-nitrosylation.
Conclusions:
- F-actin-coated microparticles (Ph+MPs) are alarmins that contribute to the proinflammatory state in diabetes mellitus.
- NOS1AP serves as a crucial link between PS-binding receptors and intracellular signaling proteins in neutrophils.
- Elevated Ph+MPs are associated with DM and are particularly high in patients with DM-related lower-extremity ulcers.
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