Mij
Senior Member (Voting Rights)
Significance
NAD+ has emerged as an important cofactor that can rewire metabolism and link energy status with cellular immune response reprogramming, raising the possibility that an improved understanding of NAD+ immunometabolic function in neuroinflammation could be exploited therapeutically.
We have now identified the enzymes NAMPT, CD38, and the transcription factor NFATC3 as critical nodes in regulating astrocyte pathogenicity and controlling experimental neuroinflammation. Importantly, we have corroborated these murine findings in human astrocytes and analysis of MS brain samples. Overall, our results describe the role of NAD+ metabolism in the local immune response in the CNS and reveal targetable mechanistic insights into how NAD+ immunometabolic signaling controls astrocyte activation and promotes CNS autoimmunity.
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).
Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive.
Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme involved in cellular redox reactions and a substrate for NAD+-dependent enzymes. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with inflammation and disease. Here, we demonstrate that cell-autonomous generation of NAD+ via the salvage pathway regulates astrocyte immune function. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the salvage pathway, results in depletion of NAD+, inhibits oxidative phosphorylation, and limits astrocyte inflammatory potential. We identified CD38 as the main NADase up-regulated in reactive mouse and human astrocytes in models of neuroinflammation and MS. Genetic or pharmacological blockade of astrocyte CD38 activity augmented NAD+ levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential to inflammatory monocytes, and ameliorated EAE.
We found that CD38 activity is mediated via calcineurin/NFAT signaling in mouse and human reactive astrocytes. Thus, NAMPT–NAD+–CD38 circuitry in astrocytes controls their ability to meet their energy demands and drives the expression of proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, MS. Our results identify candidate therapeutic targets in MS.
https://www.pnas.org/doi/10.1073/pnas.2211310119
NAD+ has emerged as an important cofactor that can rewire metabolism and link energy status with cellular immune response reprogramming, raising the possibility that an improved understanding of NAD+ immunometabolic function in neuroinflammation could be exploited therapeutically.
We have now identified the enzymes NAMPT, CD38, and the transcription factor NFATC3 as critical nodes in regulating astrocyte pathogenicity and controlling experimental neuroinflammation. Importantly, we have corroborated these murine findings in human astrocytes and analysis of MS brain samples. Overall, our results describe the role of NAD+ metabolism in the local immune response in the CNS and reveal targetable mechanistic insights into how NAD+ immunometabolic signaling controls astrocyte activation and promotes CNS autoimmunity.
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).
Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive.
Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme involved in cellular redox reactions and a substrate for NAD+-dependent enzymes. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with inflammation and disease. Here, we demonstrate that cell-autonomous generation of NAD+ via the salvage pathway regulates astrocyte immune function. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the salvage pathway, results in depletion of NAD+, inhibits oxidative phosphorylation, and limits astrocyte inflammatory potential. We identified CD38 as the main NADase up-regulated in reactive mouse and human astrocytes in models of neuroinflammation and MS. Genetic or pharmacological blockade of astrocyte CD38 activity augmented NAD+ levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential to inflammatory monocytes, and ameliorated EAE.
We found that CD38 activity is mediated via calcineurin/NFAT signaling in mouse and human reactive astrocytes. Thus, NAMPT–NAD+–CD38 circuitry in astrocytes controls their ability to meet their energy demands and drives the expression of proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, MS. Our results identify candidate therapeutic targets in MS.
https://www.pnas.org/doi/10.1073/pnas.2211310119
