Delineating the dynamics of neutrophil response in multiple inflammatory stimuli and its consequences

Abstract

In this thesis, we investigate the regulation of neutrophils, an important component of the immune system, and its implications on inflammation and pathological conditions. We use biomaterial implants to induce chronic sterile inflammation in mice and examine the effects on neutrophil production rates, maturation times, and lifespan in various tissue compartments. We demonstrate that in case where inflammation leads to emergency granulopoiesis (EG), we observe increased neutrophils progenitors, reduced maturation time in the bone marrow, reduced lifespan in circulation, and prolonged residence time at the inflammatory site. These changes aim to maintain high neutrophil numbers at the site of inflammation while keeping the circulating neutrophil count constant. However, this also results in an increase in immature neutrophils in circulation. Next, we explore the response of neutrophils to a second inflammation in mice undergoing EG. In a PVA sponge model of second inflammation, we observe increased presence of immature neutrophils and CD38+ M1-type macrophages at the second inflammatory site, indicating heightened inflammatory reactions. Next, a lung inflammation model is employed to mimic a clinically relevant scenario, again showing increased infiltration of immature neutrophils, and CD38-expressing M1-type macrophages in the lungs of mice with EG, which correlates with increased lung damage over time. Although the exact mechanism remains to be determined, the initial data suggests that inflammatory responses are intensified at the second inflammation site in mice with EG. Lastly, our study demonstrates that while the phenotype and numbers of neutrophils are altered in mice with EG, they still possess the ability to eliminate bacteria in the presence of bacterial infections at the second inflammation site. In conclusion, the research highlights the alterations in neutrophil phenotype, numbers, and function following high-grade inflammatory insults, which subsequently impact the innate immune response to a second inflammation, resulting in similar bacterial control but increased immunopathology.