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PNAS 105 (47): 18478-18483

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

Eosinophil granules function extracellularly as receptor-mediated secretory organelles

Josiane S. Nevesa,1, Sandra A. C. Pereza,b,1, Lisa A. Spencera, Rossana C. N. Meloa,c,d, Lauren Reynoldsa, Ionita Ghirana, Salahaddin Mahmudi-Azere, Solomon O. Odemuyiwae, Ann M. Dvorakd, Redwan Moqbele,2, and Peter F. Wellera,2,3

Departments of aMedicine and dPathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215; bLaboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, 21045-900, Brazil; cDepartment of Biology, Federal University of Juiz de Fora Juiz de Fora, MG, 36036-330 Brazil; and ePulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

Edited by K. Frank Austen, Brigham and Women's Hospital, Boston, MA, and approved September 29, 2008

Received for publication May 12, 2008.

Abstract: Intracellular granules in several types of leukocytes contain preformed proteins whose secretions contribute to immune and inflammatory functions of leukocytes, including eosinophils, cells notably associated with asthma, allergic inflammation, and helminthic infections. Cytokines and chemokines typically elicit extracellular secretion of granule proteins by engaging receptors expressed externally on the plasma membranes of cells, including eosinophils. Eosinophil granules, in addition to being intracellular organelles, are found as intact membrane-bound structures extracellularly in tissue sites of eosinophil-associated diseases. Neither the secretory capacities of cell-free eosinophil granules nor the presence of functional cytokine and chemokine receptors on membranes of leukocyte granules have been recognized. Here, we show that granules of human eosinophils express membrane receptors for a cytokine, IFN-{gamma}, and G protein–coupled membrane receptors for a chemokine, eotaxin, and that these receptors function by activating signal-transducing pathways within granules to elicit secretion from within granules. Capacities of intracellular granule organelles to function autonomously outside of eosinophils as independent, ligand-responsive, secretion-competent structures constitute a novel postcytolytic mechanism for regulated secretion of eosinophil granule proteins that may contribute to eosinophil-mediated inflammation and immunomodulation.

Key Words: allergy • specific • eotaxin • IFN-{gamma}


Author contributions: J.S.N., S.A.C.P., S.M.-A., S.O.O., A.M.D., R.M., and P.F.W. designed research; J.S.N., S.A.C.P., L.A.S., R.C.N.M., L.R., and I.G. performed research; J.S.N., S.A.C.P., R.M., and P.F.W. analyzed data; and J.S.N., R.M., and P.F.W. wrote the paper.

1J.S.N. and S.A.C.P. contributed equally to this work.

2R.M. and P.F.W. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0804547105/DCSupplemental.

3To whom correspondence should be addressed. E-mail: pweller{at}bidmc.harvard.edu

© 2008 by The National Academy of Sciences of the USA


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