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Published on: December 26, 2017
Aging affects the responsiveness of rat peritoneal macrophages to GM-CSF and IL-4
Mirjana Dimitrijević1, Stanislava Stanojević2, Veljko Blagojević2
1Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Despota Stefana 142, Belgrade, Serbia. miradim@sezampro.rs.
Abstract:
Macrophages undergo significant functional alterations during aging. The aim of the present study was to investigate changes of rat macrophage functions and response to M1/M2 polarization signals with age. Therefore, resident and thioglycollate-elicited peritoneal macrophages from young (3-month-old) and aged (18-19-month-old) rats were tested for phagocytic capacity and ability to secrete inflammatory mediators following in vitro stimulation with LPS and GM-CSF, and IL-4, prototypic stimulators for classically (M1) and alternatively activated (M2) macrophages, respectively. Aging increased the frequency of monocyte-derived (CCR7+ CD68+) and the most mature (CD163+ CD68+) macrophages within resident and thioglycollate-elicited peritoneal macrophages, respectively. The ability to phagocyte zymosan of none of these two cell subsets was affected by either LPS and GM-CSF or IL-4. The upregulated production of IL-1β, IL-6 and IL-10 and downregulated that of TGF-β was observed in response to LPS in resident and thioglycollate-elicited macrophages from rats of both ages. GM-CSF elevated production of IL-1β and IL-6 in resident macrophages from aged rats and in thioglycollate-elicited macrophages from young rats. Unexpectedly, IL-4 augmented production of proinflammatory mediators, IL-1β and IL-6, in resident macrophages from aged rats. In both resident and thioglycollate-elicited macrophages aging decreased NO/urea ratio, whereas LPS but not GM-SCF, shifted this ratio toward NO in the macrophages from animals of both ages. Conversely, IL-4 reduced NO/urea ratio in resident and thioglycollate-elicited macrophages from young rats only. In conclusion, our study showed that aging diminished GM-CSF-triggered polarization of elicited macrophages and caused paradoxical IL-4-driven polarization of resident macrophages toward proinflammatory M1 phenotype. This age-related deregulation of macrophage inflammatory mediator secretion and phagocytosis in response to M1/M2 activators may lead to the deficient control of infectious and/or inflammatory diseases in advanced age.
Insights
Aging alters macrophage function, decreasing GM-CSF polarization and paradoxically promoting M1 polarization with IL-4 in resident macrophages. This age-related deregulation may impair immune responses in older individuals.
Area of Science:
- Immunology
- Aging Research
- Cell Biology
Background:
- Macrophages are critical immune cells that undergo functional changes with age.
- Understanding age-related alterations in macrophage polarization is essential for addressing immune dysfunction in the elderly.
Purpose of the Study:
- To investigate age-associated changes in rat macrophage function.
- To examine the response of macrophages from young and aged rats to M1 and M2 polarization signals.
Main Methods:
- Resident and elicited peritoneal macrophages from young and aged rats were isolated.
- Cells were stimulated in vitro with lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4).
- Phagocytic capacity and inflammatory mediator secretion (IL-1β, IL-6, IL-10, TGF-β, NO/urea ratio) were assessed.
Main Results:
- Aging increased the frequency of mature macrophage subsets.
- LPS upregulated IL-1β, IL-6, and IL-10, while downregulating TGF-β, irrespective of age.
- GM-CSF enhanced IL-1β and IL-6 in aged resident macrophages and young elicited macrophages; IL-4 unexpectedly increased pro-inflammatory mediators in aged resident macrophages.
Conclusions:
- Aging impairs GM-CSF-induced polarization of elicited macrophages.
- Aging induces a paradoxical pro-inflammatory M1 polarization in resident macrophages upon IL-4 stimulation.
- Age-related deregulation of macrophage responses to polarization stimuli may compromise immune defense against infections and inflammation in older adults.
