Altered Innate Immune Functioning of Dendritic Cells in Elderly Humans: A Role of Phosphoinositide 3-Kinase-Signaling Pathway

TLDR

Aging is characterized by chronic inflammation and declining immune responses, yet dendritic cell functions in the elderly remain poorly understood. The study aimed to compare the innate immune functions of monocyte‑derived myeloid dendritic cells from elderly subjects with those from young individuals. The comparison assessed phagocytosis, migration, cytokine secretion, AKT phosphorylation, and PTEN expression in the two groups. Elderly dendritic cells displayed reduced phagocytosis and migration, heightened TNF‑α and IL‑6 secretion, diminished AKT phosphorylation, and elevated PTEN expression, indicating PI3K‑signaling impairment underlying their altered innate immune function.

Abstract

Abstract 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-3β and stromal cell-derived factor-1; and 3) significantly increased LPS and ssRNA-induced secretion of TNF-α 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.