Fueling the flame: bioenergy couples metabolism and inflammation

Abstract

We review the emerging concept that changes in cellular bioenergetics concomitantly reprogram inflammatory and metabolic responses. The molecular pathways of this integrative process modify innate and adaptive immune reactions associated with inflammation, as well as influencing the physiology of adjacent tissue and organs. The initiating proinflammatory phase of inflammation is anabolic and requires glucose as the primary fuel, whereas the opposing adaptation phase is catabolic and requires fatty acid oxidation. The fuel switch to fatty acid oxidation depends on the sensing of AMP and NAD(+) by AMPK and the SirT family of deacetylases (e.g., SirT1, -6, and -3), respectively, which couple inflammation and metabolism by chromatin and protein reprogramming. The AMP-AMPK/NAD(+)-SirT axis proceeds sequentially during acute systemic inflammation associated with sepsis but ceases during chronic inflammation associated with diabetes, obesity, and atherosclerosis. Rebalancing bioenergetics resolves inflammation. Manipulating cellular bioenergetics is identifying new ways to treat inflammatory and immune diseases.

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

“…[56][57][58][59] In this regard, gestational exposure to the viral mimetic poly(I:C) in rodents resulted in ASD-like behavioral abnormalities in the progeny, 60 and immune cells from the same animals had OXPHOS deficits still present in adulthood. 61 These findings are consistent with the current view of chronic inflammation in which the proinflammatory-phase response (mainly fueled by ATP generated in glycolysis 13 ) predominates and persists unless external changes are implemented. 62 In our study, the frequency of children (for whom all outcomes were available) having both autism and concurrent deficits in OXPHOS, immune response, and antioxidant response (considering values outside the 95% confidence interval) was 6 out of 8, supporting the concept that immunity and response to oxidative stress are interconnected and that they may be regulated by basic mitochondrial functions as part of an integrated metabolic network.…”

“…Thus, we explored the possibility that these pathways could be conceived as part of a common, integrated mechanism in which basic mitochondrial functions would play a central role. [12][13][14][15] To this end, oxidative phosphorylation (OXPHOS) capacity, immune response to phorbol 12-myristate 13-acetate (PMA), and markers of oxidative stress (reactive oxygen species [ROS] production, mitochrondrial DNA [mtDNA] deletions) were evaluated in granulocytes from children with autism and typically developing (TD) age-and gender-matched children. Although the choice of studying peripheral blood mononuclear cells (PBMCs) as a biological material could be criticized in the context of autism research, several reports have confirmed the use of PBMC gene expression as a valid surrogate for gene expression in the brain.…”

Mitochondria and AMP-activated Protein Kinase-dependent Mechanism of Efferocytosis

“…Although the beneficial effects of activated AMPK are mediated by the regulation of lipid and glucose metabolism, recent studies highlight the importance of AMPK in the inflammatory setting (21)(22)(23)(24)(25). For example, the AMPK activators metformin or 5-amino-4-imidazolecarboxamide ribonucleotide decrease neutrophil or macrophage proinflammatory action and diminish the severity of endotoxin-induced organ injury in the lungs and liver (22,26).…”

The controversy over H5N1 transmissibility research

“…Nonetheless, they cannot explain why an inactivated H5N1 virus can cause fatal acute lung injury in mice, 60 nor why survival in the acute lung injury seen in sepsis, pneumonia and influenza is determined by active resolution of inflammation, 61,62 the restoration of pulmonary endothelial barrier integrity, 63 mitochondrial biogenesis [64][65][66] and changes in energy metabolism. 67,68 Most of all, of virus were very high (LD 100 ) and there was clear evidence that after one or two days the mice stopped eating, and therefore were no longer being treated. 81 In a much larger study, several different statins were tested against several different influenza viruses in BALB/c mice.…”