Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation

Linnerbauer, Mathias; Lößlein, Lena; Vandrey, Oliver; Tsaktanis, Thanos; Beer, Alexander R.; Naumann, Ulrike; Panier, Franziska; Beyer, Tobias A.; Nirschl, Lucy; Kuramatsu, Joji B.; Winkler, Jürgen; Quintana, Francisco J.; Rothhammer, Veit

doi:10.1172/jci.insight.154824

Cited by 9 publications

(4 citation statements)

References 30 publications

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“…Intriguingly, all these pathways were down-regulated in the mutant retinas, in line with the general assumption from literature that wolframin loss impairs the cellular stress-coping capacities. On the contrary, mutant retinas upregulated key genes of neuroinflammatory pathways ( Figure 3C ) as those associated with reactive glial cells like, Gfap , Lcn2 , Edn2 , Alpk1, and C4 ( Figure 3D ; Liu et al, 2022 ; Linnerbauer et al, 2022 ). We, next, performed immunocytochemical analysis confirming the aberrant activation of the ER stress effectors ATF6 ( WT : 0.5±0.3; Wfs1 -KO: 1.5±0.2) and CHOP ( WT : 0.2±0.01; Wfs1 -KO: 0.4±0.02) in mutant retinal samples ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

Rossi

Ordazzo

Vanni

et al. 2023

eLife

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Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the WFS1 gene leading to a wide spectrum of clinical dysfunctions, among which blindness, diabetes and neurological deficits are the most prominent. WFS1 encodes for the endoplasmic reticulum (ER) resident transmembrane protein wolframin with multiple functions in ER processes. However, the WFS1-dependent etiopathology in retinal cells is unknown. Herein, we showed that Wfs1 mutant mice developed early retinal electrophysiological impairments followed by marked visual loss. Interestingly, axons and myelin disruption in the optic nerve preceded the degeneration of the retinal ganglion cell bodies in the retina. Transcriptomics at pre-degenerative stage revealed the STAT3-dependent activation of proinflammatory glial markers with reduction of the homeostatic and pro-survival factors glutamine synthetase and BDNF. Furthermore, label-free comparative proteomics identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner basigin that are highly enriched on retinal glia and myelin-forming oligodendrocytes in optic nerve together with wolframin. Loss of MCT1 caused a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state. Thus, this bioenergetic impairment is occurring concurrently both within the axonal regions and cell bodies of the retinal ganglion cells, selectively endangering their survival while impacting less on other retinal cells. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time-window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.

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Section: Resultsmentioning

confidence: 99%

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

Rossi

Ordazzo

Vanni

et al. 2023

eLife

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“…S3 A ). Notably, intranasal drug administration is highly efficient in circumventing the BBB to deliver therapeutic targets to the CNS ( 45 , 46 ) and is an effective route to transport NAD + to the brain ( 47 – 49 ). Taken together, these data suggest that NAD + bioavailability, controlled by the cross-talk between CD38 and NAMPT, regulates astrocyte activation.…”

Section: Resultsmentioning

confidence: 99%

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

Meyer

Shimon

Youssef

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…Data were analyzed using the OMIQ platform as previously described 52 . In brief, cells were gated as described previously 54 , 60 ; see also Extended Data Figs. 3a and 8a .…”

Section: Methodsmentioning

confidence: 99%

The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

Linnerbauer,

Lößlein,

Vandrey

et al. 2024

Nat Immunol

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Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.

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Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation

Cited by 9 publications

References 30 publications

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

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

The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

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Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation

Cited by 9 publications

References 30 publications

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

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

The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

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