NAD ⁺ metabolism drives astrocyte proinflammatory reprogramming in central nervous system 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.

Functional identification of soluble uric acid as an endogenous inhibitor of CD38

“…We identified a unique sUA-CD38 interaction in this study, highlighting the physiologically essential role of sUA as a purine metabolite in sustaining life. Accumulated data suggest a remarkable overlap between the effects of sUA (8-10, 15-20, 45, 46) and CD38 inhibition/KO (21, 23, 67, 68) in counteracting inflammation, aging, and certain diseases, which also strongly supports our current findings. It should be noticed that we used an exogenous compound as the background in mice to mimic the deficiency of uricase in humans, and tissue sUA levels were unchanged after sUA supplementation, suggesting some of the limitations in our models when evaluating the physiological relevance.…”

“…In addition, our findings also provide biological evidence for the neuroprotection of sUA. It has been reported that CD38 is involved in neurodegenerative diseases (67, 68), thus, sUA in central nervous system (CNS) tissues may directly inhibit CD38 activity to limit neuroinflammation and the progression of such diseases.…”

“…In addition to enzymatic activity, CD38 may also serve as a receptor for adhesion molecules such as CD31 to regulate cell migration and homing 25,26 . Inhibition or deficiency of CD38 suppresses inflammation 27 , aging-related dysfunction 22,23 , and the progression of neurodegenerative diseases such as Alzheimer's disease 28 and multiple sclerosis 29 . Clinical observations 30,31 and experimental evidence 12,[32][33][34] suggest similar protective effects of sUA.…”

Heavy-chain antibody targeting of CD38 NAD+ hydrolase ectoenzyme to prevent fibrosis in multiple organs

“…Indeed, the expression of CD38 is elevated in multiple tissues and cell types during aging, which is largely attributable to its induction by SASP 11 , 27 . Additionally, CD38 is upregulated in the heart following ischemia–reperfusion injury, the CNS in a variety of neurodegenerative and neuroinflammatory diseases, in tumorigenesis, and in muscle, liver and articular cartilage during aging 11 , 31 , 53 , 54 .…”

NAD+depletion and altered mitochondrial function are key to the establishment of placental dysfunction in an inflammatory-driven subclass of preeclampsia

“…There is strong evidence to suggest that placental mitochondrial dysfunction may be a common feature across all PE subclasses [8], however a lack of subclass-specific research endeavours has limited our current understanding of this pathology, specifically in the context of inflammation-driven PE. In non-pregnant populations, several inflammatory disease conditions have been tightly linked to mitochondrial dysfunction, in large part driven by profound overactivity of nicotinamide adenine dinucleotide (NAD + ) consuming enzymes, leading to depletion of intracellular NAD + stores [16][17][18][19][20][21][22][23][24][25][26][27][28]. In the current study, this body of work will be expanded to determine if NAD + depletion may likewise initiate placental mitochondrial dysfunction in inflammation-mediated PE.…”