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.

Figure 1.. Inflammation processes.

(A) Acute systemic inflammation switches from the proinflammatory phase to the adaptation phase and eventually progresses to resolution. (B) Chronic inflammation sustains a proinflammatory phase.

Figure 2.. Epigenetic reprogramming of inflammatory genes.

(A) Proinflammatory phase requires p65, and adaptation phase requires RelB epigenetic silencing during acute systemic inflammation. (B) Chronic inflammation does not deactivate p65 nor develop an appropriate opposing adaptation phase. Green, Quiescent state; red, proinflammatory phase; blue, adaptation phase.

Figure 3.. Metabolic regulation of inflammation.

The proinflammatory phase requires HIF-1α-dependent glycolysis, and adaptation phase requires PGC-1-dependent fatty acid oxidation and mitochondrial biogenesis. Red, Proinflammatory phase; blue, adaptation phase. PFK1, Phosphofructokinase-1; PK, pyruvate kinase; Ac-CoA, acetyl CoA; TCA, tricarboxylic acid; ACS, acyl-CoA synthetase; CPT-1, carnitine palmitoyltransferase 1.

Figure 4.. NAD⁺ generation by rate-limiting NAMPT.

Red, proinflammatory phase; blue, adaptation phase.

Figure 5.. Bioenergy sensing by SirTs and AMPK regulate mitochondrial respiration, mitochondrial biogenesis, glycolysis, and fatty acid oxidation.

Figure 6.. Bioenergy coordinates metabolic and inflammatory responses.

SirT sensors of NAD⁺ provide an axis that integrates glycolysis and proinflammation with fatty acid oxidation and adaptation responses, which oppose the proinflammatory state and support restoration and resolution. GO, Glucose oxidation; FAO, fatty acid oxidation. Red, Proinflammatory phase; blue, Adaptation phase.