Does dysregulation of redox state underpin the decline of innate immunity with aging?

Griffiths, Helen R. and Rooney, Matthew C.O. and Perrie, Yvonne (2020) Does dysregulation of redox state underpin the decline of innate immunity with aging? Antioxidant and Redox Signalling, 32 (13). pp. 1014-1030. ISSN 1557-7716

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    Significance: Antibacterial defense invokes the innate immune system as a first responder, with neutrophils phagocytozing and forming neutrophil extracellular traps around pathogens in a reactive oxygen species (ROS)-dependent manner. Increased NOX2 activity and mitochondrial ROS production in phagocytic, antigen-presenting cells (APCs) affect local cytokine secretion and proteolysis of antigens for presentation to T cells at the immune synapse. Uncontrolled oxidative post-translational modifications to surface and cytoplasmic proteins in APCs during aging can impair innate immunity. Recent Advances: NOX2 plays a role in the maturation of dendritic cells, but paradoxically NOX2 activity has also been shown to promote viral pathogenicity. Accumulating evidence suggests that a reducing environment is essential to inhibit pathogen proliferation, facilitate antigenic processing in the endosomal lumen, and enable an effective immune synapse between APCs and T cells. This suggests that the kinetics and location of ROS production and reducing potential are important for effective innate immunity. Critical Issues: During aging, innate immune cells are less well able to phagocytoze, kill bacteria/viruses, and process proteins into antigenic peptides?three key steps that are necessary for developing a specific targeted response to protect against future exposure. Aberrant control of ROS production and impaired Nrf2-dependent reducing potential may contribute to age-associated immune decline. Future Directions: Local changes in redox potential may be achieved through adjuvant formulations to improve innate immunity. Further work is needed to understand the timing of delivery for redox modulators to facilitate innate immune cell recruitment, survival, antigen processing and presentation activity without disrupting essential ROS-dependent bacterial killing.