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*Institut für klinische Transfusionsmedizin und Immungenetik Ulm, Institut für Transfusionsmedizin Universitat Ulm, Ulm, Germany,
Laboratory of Cell Biology, Instituto Nationale per la Ricerca sul Cancro, Genova, Italy,
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, AZ 85259; and
¶Amnis Corporation, Seattle, WA 98121
Eosinophils (Eos) are found at increased numbers within necrotic areas of tumors. We show that necrotic material from cell lysates containing damage-associated molecular pattern molecules induce eosinophil degranulation (release of major basic protein and eosinophil peroxidase) and enhance their oxidative burst while the stimulatory capacity of cell lysates is significantly diminished following oxidation. High mobility group box 1 (HMGB1), a prototypic damage-associated molecular pattern molecule, released following necrosis but not apoptosis, induced a similar effect on Eos. Additionally, we demonstrate that HMGB1 enhances eosinophil survival and acts as a chemoattractant. Consistently, we show that Eos express an HMGB1 receptor, the receptor for advanced glycation end product, and that anti-receptor for advanced glycation end product could diminish the HMGB1-mediated effects. Of all tested biologic activities, Eos respond most sensitively to the presence of necrotic material including HMGB1 with generation of peroxide. We postulate that Eos "sense" necrotic cell death, migrating to and responding to areas of tissue injury/necrosis. Oxidation of cell lysates reduces their biologic activity when compared with native lysates. We postulate that eosinophil-associated modulation of immunity within tumor and other damaged tissues may be primarily by promoting oxidative degradation of necrotic material. Novel therapeutic strategies may be considered by advancing oxidative denaturation of released necrotic material using Eos or other aerobic strategies.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 R.L. and M.T.L. designed and conducted the research, analyzed the data and wrote the article; G.I.H. performed the oxidative burst and degranulation assays; D.B.S. produced electron microscopic and confocal images; R.A.D. purified HMGB1 and produced specific antibodies to HMGB1; A.R., J.J.L., and H.S. helped in writing the article and provided important advice; and all authors contributed to critical review of the article.
2 Address correspondence and reprint requests to Dr. Michael Lotze, University of Pittsburgh, W1540 Biomedical Science Tower, Pittsburgh, PA 15261. E-mail address: lotzemt{at}upmc.edu
3 Abbreviations used in this paper: DAMP, damage associated molecular pattern molecule; HMGB1, high mobility group box 1; Eos, eosinophil; Gr, granulocyte; MSC, mesenchymal stem cell; F/T, freeze/thaw; EPO, eosinophil peroxidase; RAGE, receptor for advanced glycation end product; MBP, major basic protein; DC, dendritic cell.
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