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

Griffiths, Helen, Rooney, Matt and Perrie, Yvonne (2020) Does dysregulation of redox state underpin the decline of innate immunity with ageing? Antioxidants and Redox Signaling.

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Significance Anti-bacterial defence invokes the innate immune system as a first responder, with neutrophils phagocytosing and forming NETs around pathogens in a ROS-dependent manner. Increased NOX2 activity and mitochondrial ROS production in phagocytic, antigen-presenting cells affects 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 antigen presenting cells during ageing 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 antigen presenting cells 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 ageing, innate immune cells are less well able to phagocytose, 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. Innovation Immune memory of a pathogen depends on recognition of a unique antigenic “mark” or epitope on the pathogen. It requires carefully orchestrated interactions between the memory-holding lymphocytes in the adaptive arm of immune system, and the antigen presenting innate immune cells. The uptake and processing of pathogens to produce unique antigenic “marks” by macrophages and dendritic cells is modulated by redox state. With ageing-associated dysregulation of redox state, impaired immune memory may ensue. Approaches to manipulate redox state in specific subcellular endosomal compartments after antigen uptake should be explored to understand whether vaccination responses may be improved during ageing.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Perrie, Yvonne
Date : 28 January 2020
DOI : doi.10.1089/ars.2020.8021
Uncontrolled Keywords : reactive oxygen species, dendritic cell, glutathione, peptide antigen, vaccine
Depositing User : James Marshall
Date Deposited : 18 Feb 2020 15:00
Last Modified : 17 Mar 2020 09:52

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