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* Division of Basic and Clinical Immunology, University of California, Irvine, CA 92697; and
Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA 92697
Aging represents a state of paradox where chronic inflammation is associated with declining immune responses. Dendritic cells (DCs) are the major APCs responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. In this study, we have compared the innate immune functions of monocyte-derived myeloid DCs from elderly subjects with DCs from young individuals. We show that although phenotypically comparable, DCs from the aging are functionally different from DCs from the young. In contrast to DCs from the young, DCs from elderly individuals display 1) significantly reduced capacity to phagocytose Ags via macropinocytosis and endocytosis as determined by flow cytometry; 2) impaired capacity to migrate in vitro in response to the chemokines MIP-3
and stromal cell-derived factor-1; and 3) significantly increased LPS and ssRNA-induced secretion of TNF-
and IL-6, as determined by ELISA. Investigations of intracellular signaling revealed reduced phosphorylation of AKT in DCs from the aging, indirectly suggesting decreased activation of the PI3K pathway. Because the PI3K-signaling pathway plays a positive regulatory role in phagocytosis and migration, and also functions as a negative regulator of TLR signaling by inducing activation of p38 MAPK, this may explain the aberrant innate immune functioning of DCs from elderly subjects. Results from real-time PCR and protein expression by flow cytometry demonstrated an increased expression of phosphatase and tensin homolog, a negative regulator of the PI3K-signaling pathway, in DCs from the aging. Increased phosphatase and tensin homolog may thus be responsible for the defect in AKT phosphorylation and, therefore, the altered innate immune response of DCs from elderly humans.
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 This work supported in part by National Institutes of Health Grant AG027512 and partly by a New Scholar Grant from the Ellison Medical Foundation.
2 Address correspondence and reprint requests to Dr. Anshu Agrawal, Division of Basic and Clinical Immunology, Medical Sciences I, C-240A, University of California, Irvine, CA 92697. E-mail address: aagrawal{at}uci.edu
3 Abbreviations used in this paper: DC, dendritic cell; MDDC, monocyte-derived DC; SDF-1, stromal cell-derived factor-1; LU, Lucifer Yellow; FITC-DEX, FITC-conjugated dextran; MR, mannose receptor; PTEN, phosphatase and tensin homolog.
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