Redox regulation in metabolic programming and inflammation


Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs. Later on, the most prevalent recruited innate immune cells are monocytes. Their role is to complete a damage limitation exercise initiated by neutrophils and then, as re-programmed M2 macrophages, to resolve the inflammatory event. Almost twenty five years ago, it was noted that macrophages lose their glycolytic capacity and become anti-inflammatory after treatment with corticosteroids. In support of this we now understand that, in contrast to early responders, M2 macrophages are predominantly dependent on oxidative phosphorylation for energy. During early inflammation, polarisation towards M1 macrophages is dependent on NOX2 activation which, via protein tyrosine phosphatase oxidation and AKT activation, increases trafficking of glucose transporters to the membrane and consequently increases glucose uptake for glycolysis. In parallel, mitochondrial efficiency is likely to be compromised via nitrosylation of the electron transport chain. Resolution of inflammation is triggered by encounter with apoptotic membranes exposing oxidised phosphatidylserine that interact with the scavenger receptor, CD36. Downstream of CD36, activation of AMPK and PPARγ elicits mitochondrial biogenesis, arginase expression and a switch towards oxidative phosphorylation in the M2 macrophage. Proinflammatory cytokine production by M2 cells decreases, but anti-inflammatory and wound healing growth factor production is maintained to support restoration of normal function.

Publication DOI:
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
College of Health & Life Sciences > School of Biosciences
Additional Information: © 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( Funding: BBSRC (China Partnering Award BB/M028100/1 and Targeted Priority Studentship in Ageing BB/G017832/1); and the Glenn Foundation for Aging Research.
Uncontrolled Keywords: Biochemistry,Organic Chemistry
Publication ISSN: 2213-2317
Last Modified: 19 Feb 2024 08:13
Date Deposited: 06 Apr 2017 12:45
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Review article
Published Date: 2017-08
Published Online Date: 2017-02-12
Accepted Date: 2017-01-31
Submitted Date: 2017-01-05
Authors: Griffiths, Helen R. (ORCID Profile 0000-0002-2666-2147)
Gao, Dan
Pararasa, Chathyan

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