|Fig. 1 from the McGettrick and O’Neill minireview in The Journal of Biological Chemistry: succinate is a signal generated in response to activation of TLR4 by LPS, leading to HIF1α activation.
In The Journal of Biological Chemistry, molecular immunologists Anne McGettrick and Luke O’Neill of Trinity College, Dublin, review recent work investigating how the innate immune-response system, the first-responder mechanism against invading pathogens, is coupled to metabolic signaling. This research has implications for understanding the progression of type 2 diabetes, atherosclerosis and other metabolic disorders.
In the minireview, McGettrick and O’Neill cover work from their own laboratories as well as others to highlight how activation of the innate immune system via Toll-like and NOD-like receptors induces a variety of metabolic changes necessary for a sustained, effective immune response.
Toll-like receptor 4 activation by Gram-negative bacteria lipopolysaccharide alters glutamine metabolism, causing an increase in intracellular succinate. Increased levels of succinate lead to the stabilization of the stress-related transcription factor hypoxia-inducible factor 1-α and activation of transcription of pro-inflammatory cytokines, such as interleukin-1β.
In the case of NOD-like receptor protein 3, induction of the pathway begins with extracellular insults that result in a decrease in the intracellular levels of NAD+ thereby reducing the activity of the deacetylase sirtuin-2 and leading to the accumulation of acetylated tubulin. This activates NLRP3, resulting in an increase in pro-inflammatory cytokines. This NLRP3 pathway can be activated by excess dietary factors such as uric acid and low-density lipoprotein, resulting in conditions like gout and arterial plaques respectively.
The functional relationship between metabolic pathways and the innate immune system provides a foundation for understanding complex physiological processes. Whenever the innate immune system encounters cues from excess metabolites, the ordinarily beneficial physiological inflammation process is turned into pathological syndromes. A better understanding of how metabolism and innate immunity are integrated is essential to improving therapeutic approaches for metabolic diseases.