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Macrophage hypo-responsiveness to interferon-gamma in aged mice is associated with impaired signaling through
P Yoon1, K T Keylock, M E Hartman
1Department of Kinesiology, University of Illinois, 906 S. Goodwin Avenue, Urbana, IL 61801, USA.
Abstract:
Since macrophages (Mphis) are a first line of defense against pathogens, and are involved in both innate and adaptive immunity, understanding the impact of aging on Mphi function is important. In the past studies, we and others have shown that aging decreases Mphi responsiveness to classical activating signals (e.g. IFN-gamma and lipopolysaccharide, LPS). In this study, we examined the impact of aging on Mphi signaling through the IFN-gamma receptor pathway. Mphis from male Balb/c mice aged 2 (young) and 18-24 (old) months were purified and then stimulated with IFN-gamma. Western blotting revealed a significant reduction ( approximately 50%) in IFN-gamma-stimulated tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1) alpha and beta in Mphis from aged, when compared with young mice. This reduction in phospho-STAT-1 was associated with a significant constitutive reduction ( approximately 80%) in total STAT-1alpha protein and a complete inhibition of STAT-1 gene expression in response to IFN-gamma in old compared to young mice. These data may, in part, explain why classical Mphi responses like reactive nitrogen and oxygen species generation, tumor killing and microbicidal activity are lower in Mphis from aged subjects. We conclude that peritoneal Mphis from aged mice have an intrinsic defect in Jak-STAT signaling which prevents them from fully responding to IFN-gamma.
Insights
Aging impairs macrophage function by disrupting the Jak-STAT signaling pathway. This leads to reduced responsiveness to interferon-gamma (IFN-gamma), impacting immune defense in older individuals.
Area of Science:
- Immunology
- Aging research
- Cell signaling
Background:
- Macrophages (Mphis) are crucial immune cells involved in innate and adaptive immunity.
- Aging is known to decrease Mphi responsiveness to common immune activators like IFN-gamma and lipopolysaccharide (LPS).
Purpose of the Study:
- To investigate the specific impact of aging on macrophage signaling through the IFN-gamma receptor pathway.
- To elucidate the molecular mechanisms underlying age-related decline in Mphi function.
Main Methods:
- Purification of peritoneal Mphis from young (2-month-old) and old (18-24-month-old) male Balb/c mice.
- Stimulation of Mphis with IFN-gamma.
- Analysis of signal transducer and activator of transcription-1 (STAT-1) phosphorylation and expression using Western blotting.
Main Results:
- Aged Mphis showed a ~50% reduction in IFN-gamma-stimulated STAT-1 phosphorylation.
- Aged Mphis exhibited a significant constitutive reduction (~80%) in total STAT-1alpha protein.
- Complete inhibition of STAT-1 gene expression in response to IFN-gamma was observed in old Mphis compared to young Mphis.
Conclusions:
- Peritoneal Mphis from aged mice possess an intrinsic defect in Jak-STAT signaling.
- This defect impairs the ability of aged Mphis to respond effectively to IFN-gamma.
- The findings may explain age-related decreases in Mphi functions such as pathogen killing and tumor surveillance.
