[show abstract][hide abstract] ABSTRACT: Macrophages are an essential component of both innate and adaptive immunity, and altered function of these cells with aging may play a key role in immunosenescence. To determine the effect of aging on macrophages, we produced bone marrow-derived macrophages in vitro. In these conditions, we analyzed the effect of aging on macrophages without the influence of other cell types that may be affected by aging. We showed that telomeres shorten with age in macrophages leading to a decreased GM-CSF but not M-CSF-dependent proliferation of these cells as a result of decreased phosphorylation of STAT5a. Macrophages from aged mice showed increased susceptibility to oxidants and an accumulation of intracellular reactive oxygen species. In these macrophages STAT5a oxidation was reduced, which led to the decreased phosphorylation observed. Interestingly, the same cellular defects were found in macrophages from telomerase knockout (Terc(-/-)) mice suggesting that telomere loss is the cause for the enhanced oxidative stress, the reduced Stat5a oxidation and phosphorylation and, ultimately, for the impaired GM-CSF-dependent macrophage proliferation.
The Journal of Immunology 09/2009; 183(4):2356-64. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Macrophages are key cells in innate and adaptive immune function. These cells are involved in the destruction of bacteria,
parasites, viruses and tumor cells and lead to the initiation of the inflammatory process. In addition, macrophages are responsible
for processing antigens and presenting digested peptides to T-lymphocytes initiating the adaptive immune response. Finally,
macrophages participate in the resolution of the inflammatory process by promoting tissue repair. Macrophage functions are
affected by aging, thereby contributing to the immunosenescence of adaptive and innate immunity. Here, we summarize data about
the effects of aging on macrophages and we discuss the molecular events that could be involved in this process.
[show abstract][hide abstract] ABSTRACT: A senescence-accelerated (SAMP8) mouse model was used to determine the effect of aging on the immune system. We produced in vitro bone marrow-derived macrophages from SAMP8 mice and compared them against senescence-resistant, long-lived mice (SAMR1). Although macrophages from both strains of mice proliferated in a similar manner in response to monocyte-colony-stimulating factor (M-CSF), SAMP8 macrophages showed an impaired response to granulocyte macrophage-colony-stimulating factor (GM-CSF). Similar levels of external regulated kinases (ERK)1/2 and signaling transducer and activator of transcription 5 (STAT5) phosphorylation were observed in macrophages from both strains of mice. The lack of proliferation was not caused by the induction of apoptosis. Differentiation of bone marrow cells into dendritic cells was similar in both strains of mice, as was the induction of major histocompatibility complex (MHC) class II molecules by interferon-gamma (IFN-gamma). Finally, we determined the density of Langerhans cells in vivo in the skin of the two mouse strains, but no differences were found.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 12/2008; 63(11):1161-7. · 4.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: After interaction with its receptor, GM-CSF induces phosphorylation of the beta-chain in two distinct domains in macrophages. One induces activation of mitogen-activated protein kinases and the PI3K/Akt pathway, and the other induces JAK2-STAT5. In this study we describe how trichostatin A (TSA), which inhibits deacetylase activity, blocks JAK2-STAT5-dependent gene expression but not the expression of genes that depend on the signal transduction induced by the other domain of the receptor. TSA treatment inhibited the GM-CSF-dependent proliferation of macrophages by interfering with c-myc and cyclin D1 expression. However, M-CSF-dependent proliferation, which requires ERK1/2, was unaffected. Protection from apoptosis, which involves Akt phosphorylation and p21(waf-1) expression, was not modified by TSA. GM-CSF-dependent expression of MHC class II molecules was inhibited because CIITA was not induced. The generation of dendritic cells was also impaired by TSA treatment because of the inhibition of IRF4, IRF2, and RelB expression. TSA mediates its effects by preventing the recruitment of RNA polymerase II to the promoter of STAT5 target genes and by inhibiting their expression. However, this drug did not affect STAT5A or STAT5B phosphorylation or DNA binding. These results in GM-CSF-treated macrophages reveal a relationship between histone deacetylase complexes and STAT5 in the regulation of gene expression.
The Journal of Immunology 06/2008; 180(9):5898-906. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aging is associated with the deterioration of several physiological functions, which leads to aged-related pathologies and, ultimately, to death. The immune system is affected by aging, causing an increased susceptibility to infections and mortality, as well as a major incidence of immune diseases and cancer in the elderly. Because macrophages are an essential component of both innate and adaptive immunity, altered function of these phagocytic cells with aging may play a key role in immunosenescence. Here we summarize data about the effects of aging on macrophages and we discuss the molecular events that could be involved in this process.
[show abstract][hide abstract] ABSTRACT: In order to determine the effect of aging on macrophages, we produced bone marrow-derived macrophages in vitro from young and aged mice. We analyzed the effect of aging on the genomic expression of macrophages in these conditions, without the influence of other cell types that may be affected by aging. Macrophages from young and aged mice were present in similar numbers and showed an identical degree of differentiation, cell size, DNA content and cell surface markers. After incubation with interferon-gamma (IFN-gamma), the expression at the cell surface of the MHC class II gene IA complex product and the levels of intracellular IAbeta protein and mRNA were lower in aged macrophages. Moreover, the transcription of IAbeta gene was impaired in aged macrophages. The amount of transcription factors that bound to the W and X boxes, but not to the Y box of the IAbeta promoter gene were lower in aged macrophages. Similar levels of CIITA mRNA were found after IFN-gamma treatment of both young and aged macrophages. This shows that neither the initial cascade that starts after the interaction of IFN-gamma with the receptor, nor the second signals involved in the expression of CIITA, are impaired in aged macrophages. These data could explain, at least in part, the impaired immune response associated to senescence.