Autophagy is indispensable for normal maturation and function of macrophages and neutrophils

Thesis

Macrophages and neutrophils are vital cells of the immune system, performing crucial innate functions and bridging innate and adaptive immunity. However, inappropriate activation or poor resolution of responses results in chronic inflammatory and autoimmune conditions due to accumulation of myeloid cells and uncontrolled cytokine production, as is commonly seen in the aging immune system. It is not clear what is required to maintain healthy myeloid cells throughout life or what links inflammation and myeloid dysfunction during the aging process. We have shown that autophagy, a vital intracellular degradation mechanism, is required for normal macrophage innate and adaptive immune functions such as phagocytosis and antigen presentation, as well as being an important regulator of the inflammatory response. Loss of autophagy also results in reduced surface antigen expression and increased glycolysis. We found that autophagy-deficient macrophages have a similar phenotype to aged macrophages. Furthermore, aged macrophages exhibit reduced autophagy compared with young macrophages, suggesting a link between reduced autophagy and acquisition of the aging macrophage phenotype. Finally, we show that autophagy plays a vital role in normal neutrophil differentiation, with autophagy-deficient neutrophils exhibiting altered nuclear morphology and aberrant granule formation. These data show that autophagy plays a critical role in the maintenance of essential macrophage homeostasis and functions by regulating inflammation and metabolism, thereby preventing immunosenescence. We postulate that autophagy modulation in macrophages and neutrophils may be used to prevent excess inflammation, such as in inflammatory and autoimmune diseases. Moreover, inflammation due to aging may potentially be delayed by induction or preservation of autophagy, which could improve immune responses and reduce the morbidity and mortality associated with “inflamm-aging”.

Authors: Stranks, A; Amanda Stranks

• Publication date: 2013
• DOI: 10.5287/ora-kkjnmv4vy
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: immunology; aging; macrophage; autophagy; cell biology; metabolism
• Subjects: Metabolism; Cell Biology; Biology (medical sciences); Immunology