The effects of senescence and aging on geriatric diseases has been well
explored but how these influence infections in the elderly have been scarcely
addressed. Here, we show that several innate immune responses are elevated in
senescent cells and old mice, allowing them to promptly respond to bacterial
infections. We have identified higher levels of iNOS as a crucial host response
and show that p38 MAPK in senescent cells acts as a negative regulator of iNOS
transcription. In old mice, however the ability to impede bacterial
proliferation does not correlate with increased survival as elevated immune
responses persist unabated eventually affecting the host. The use of
anti-inflammatory drugs that could consequently be recommended also decreases
iNOS disarming the host of a critical innate immune response. Overall, our study
highlights that infection associated mortality in the elderly is not merely an
outcome of pathogen load but is also influenced by the host’s ability to resolve
inflammation induced damage.
Summary statement
Using cellular models and old mice we demonstrate the effect of aging on
host response to bacterial infections. Aged systems mount a more effective
anti-bacterial innate immune response but its persistence results in
mortality of the host.
Neutrophils play a crucial role in establishing inflammation in response to an infection or injury, but their production rates, as well as blood and tissue residence times, remain poorly characterized under these conditions. Herein, using a biomaterial implant model to establish inflammation followed by in vivo tracking of newly formed neutrophils, we determine neutrophil kinetics under inflammatory conditions. To obtain quantifiable information from our experimental observations, we develop an ordinary differential equation-based mathematical model to extract kinetic parameters. Our data show that in the presence of inflammation resulting in emergency granulopoiesis-like conditions, neutrophil maturation time in the bone marrow and half-life in the blood reduces by about 40%, compared to non-inflammatory conditions. Additionally, neutrophil residence time at the inflammatory site increases by two-fold. Together, these data improve our understanding of neutrophil kinetics under inflammatory conditions, which could pave the way for therapies that focus on modulating in vivo neutrophil dynamics.
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