@article{0138bd99b62948b483df45e2d4172c7b,
title = "Blood-Borne Microparticles Are an Inflammatory Stimulus in Type 2 Diabetes Mellitus",
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.",
author = "Thom, {Stephen R.} and Bhopale, {Veena M.} and Arya, {Awadhesh K.} and Deepa Ruhela and Bhat, {Abid R.} and Nandita Mitra and Ole Hoffstad and Malay, {D. Scot} and Mirza, {Ziad K.} and Lantis, {John C.} and Lev-Tov, {Hadar A.} and Kirsner, {Robert S.} and Hsia, {Ru Ching} and Levinson, {Susan L.} and DiNubile, {Mark J.} and Margolis, {David J.}",
note = "Funding Information: Address correspondence and reprint requests to: Dr. Stephen R. Thom, University of Maryland School of Medicine, Room 4-013 Bressler Research Building, 655 W. Baltimore Street, Baltimore, MD 20201. E-mail address: sthom@som.umaryland.edu ORCIDs: 0000-0002-3533-6124 (S.R.T.); 0000-0003-4476-1189 (A.R.B.); 0000-0002-7714-3910 (N.M.); 0000-0002-0261-903X (O.H.); 0000-0002-7270-1952 (Z.K.M.); 0000-0002-8449-089X (R.C.-H.); 0000-0002-0506-8085 (D.J.M.). This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes for Health (R01-DK116199 to multiple principal investigators D.J.M. and S.R.T.); National Institute of Neurological Disorders and Stroke, National Institutes for Health (R01-NS122855 to S.R.T.); and the U.S. Office of Naval Research (N00014-20-1-2641 to S.R.T.). The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication. S.R.T. conceived ideas, oversaw the research program, performed laboratory studies, analyzed data, and wrote the manuscript. V.M.B., A.K.A., D.R., and A.R.B. performed laboratory studies, reviewed the manuscript, and provided advice. N.M. and O.H. analyzed data, reviewed the manuscript, and provided advice. D.S.M., Z.K.M., J.C.L., H.A.L.-T., and R.S.K. aided with study subject recruitment, collected blood, reviewed the manuscript, and provided advice. R.-C.H. aided with sample preparation and electron microscopic imaging, reviewed the manuscript, and provided advice. S.L.L. and M.J.D. provided human recombinant gelsolin, reviewed the manuscript, and provided advice. D.J.M. conceived ideas, oversaw portions of the work, analyzed data, reviewed the manuscript, and provided advice. S.R.T. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Abbreviations used in this article: ASC, adaptor molecule apoptosis-associated speck-like protein containing a CARD; AU, arbitrary unit; cat#, catalog number; CEPC, circulating endothelial progenitor cell; DFU, diabetes mellitus and a foot ulcer; DFUC, Diabetic Foot Ulcer Consortium; DM, diabetes mellitus; KO, knockout; MP, microparticle; MPO, myeloperoxidase; NLRP3, nucleotide-binding domain leucine-rich repeat-like receptor; NOS, NO synthase; NOS1AP, NO synthase 1 adaptor protein; PC, phosphatidylcholine; Ph, phalloidin; Ph1, phalloidin positive; PS, phosphatidylserine; RAGE, receptor for advanced glycation end products; siRNA, small inhibitory RNA; SrcK, Src kinase; SSO, sulfo-N-succinyloleate. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license. Publisher Copyright: {\textcopyright} 2023 The Authors.",
year = "2023",
month = jan,
day = "1",
doi = "10.4049/immunohorizons.2200099",
language = "English",
volume = "7",
pages = "71--80",
journal = "ImmunoHorizons",
issn = "2573-7732",
publisher = "NLM (Medline)",
number = "1",
}