Blood-Borne Microparticles Are an Inflammatory Stimulus in Type 2 Diabetes Mellitus

Stephen R. Thom, Veena M. Bhopale, Awadhesh K. Arya, Deepa Ruhela, Abid R. Bhat, Nandita Mitra, Ole Hoffstad, D. Scot Malay, Ziad K. Mirza, John C. Lantis, Hadar A. Lev-Tov, Robert S. Kirsner, Ru Ching Hsia, Susan L. Levinson, Mark J. DiNubile, David J. Margolis

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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-kB 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. ImmunoHorizons, 2023, 7: 71-80.

Original languageEnglish
Pages (from-to)71-80
Number of pages10
JournalImmunoHorizons
Volume7
Issue number1
DOIs
StatePublished - 1 Jan 2023

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