Macrophages resident in the bone marrow, spleen, lung, and peritoneal cavity of elderly humans or aged animals display dysregulated functions including decreased antigen presenting capability, decreased ability to mobilize in response to tissue injury, and decreased inflammatory function in response to specific stimuli such as CD40-ligation or CD 14-ligation. Evidence is accumulating that environmental influences such as stromal function and imbalances in cytokines and growth factors, may be responsible for much of the dysfunction associated with immunosenescence. It is also known that treatment of macrophages with either type 1 (e.g., IFNgamma) or type 2 (e.g., IL-4, IL-10, TGFbeta) cytokines alters their functional responsiveness to subsequent activating stimuli. Whereas type 1 cytokines promote cytocidal and pro-inflammatory activities upon receipt of an activating signal (LPS or CD40 ligation), type 2 cytokines promote anti-inflammatory and tissue restructuring activities upon receipt of an activating signal. This proposal examines the hypotheses (1) that the macrophage dysfunction observed in aged animals and humans may be a polarization of the macrophages to type 2-cytokine promoted functions as opposed to the classical type 1 cytokine promoted functions, (2) that the apparent macrophage dysfunction or polarization is the reversible result of cytokine imbalance in the microenvironment rather than due to inherent irreversible defects in the myeloid lineage, and (3) that correction of the cytokine imbalance may improve macrophage function. The phenotype and pattern of inducible activities of resident macrophages will be assessed to determine if the macrophages from aged animals are generally hyporesponsive to stimuli or are polarized in the pattern of their functional response to stimuli. The influence of the aged environment on these macrophages will be assessed by removing the macrophages from the aged animals to determine if the functional response pattern observed in young mice is partially or completely restored. Finally, the efficacy of treatment of mice with type 1 cytokine agonists and type 2 cytokine antagonists in restoring type 1 macrophage functions will be assessed. Overall, these studies will increase our understanding of age-related dysregulation of macrophage function and provide possible avenues of therapeutic intervention which may enhance macrophage function in the elderly, thus improving their ability to resist infectious disease.
| Stout, Robert D; Suttles, Jill (2005) Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev 205:60-71 |
| Stout, Robert D; Jiang, Chuancang; Matta, Bharati et al. (2005) Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 175:342-9 |
| Stout, Robert D; Suttles, Jill (2004) Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 76:509-13 |
