NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

Alami, Najwa Ouali; Schurr, Christine; Heuvel, Florian olde; Tang, Linyun; Li, Qian; Tasdogan, Alpaslan; Kimbara, Atsushi; Nettekoven, Matthias; Ottaviani, Giorgio; Raposo, Catarina; Röver, Stephan; Rogers‐Evans, Mark; Rothenhäusler, Benno; Ullmer, Christoph; Fingerle, Jürgen; Grether, Uwe; Knuesel, Irène; Boeckers, Tobias M.; Ludolph, Albert C.; Wirth, Thomas; Roselli, Francesco; Baumann, Bernd

doi:10.15252/embj.201798697

Cited by 126 publications

(134 citation statements)

References 65 publications

(111 reference statements)

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“…Interestingly, NF‐κB that was recognized to be a histamine‐related gene complex by our multi‐omics pathway analysis was also found dysregulated in our cohort of sALS patients, thus making it a likely target of histamine intervention. Because activation of NF‐κB during the early phases of ALS is sufficient to prolong survival in mice, whereas activation in glia in the late phases decreases survival, a therapy able to inhibit NF‐κB at symptomatic phase is predicted to be beneficial, as indeed we obtained here with histidine. The levels of phosphorylated AKT in motor neurons are decreased in ALS patients and SOD1‐G93A mice .…”

Section: Discussionsupporting

confidence: 60%

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Apolloni

Amadio

Fabbrizio

et al. 2019

J cachexia sarcopenia muscle

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Background Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti‐inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine‐mediated therapeutic strategy in ALS mice. Methods We adopted an integrative multi‐omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)‐G93A mice that recapitulate key ALS features, with the brain‐permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1‐G93A motor neuron‐like cells. Results We identified 13 histamine‐related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine‐related genes overlapped with genomic regions disrupted by DNA copy number and with ALS‐linked pathogenic variants. Histidine treatment in SOD1‐G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro . Conclusions Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine‐related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi‐gene network responsible for ALS and, furthermore, in the drug development process.

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Section: Discussionsupporting

confidence: 60%

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Apolloni

Amadio

Fabbrizio

et al. 2019

J cachexia sarcopenia muscle

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“…Indeed, reactive astrocytes overexpress many cytokines, chemokines, and signaling molecules that could activate neighboring microglial cells Zamanian et al, 2012), see Figure 2l]. Astrocyte-specific NF-κB activation induces significant astrocyte reaction that secondarily causes microglia activation (Oeckl et al, 2012;Ouali Alami et al, 2018).…”

Section: How Do Reactive Astrocytes Interact With Other Innate Immumentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

220

180

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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“…For instance, hallmarks of astrocyte activation feature prominently in post-mortem tissues from amyotrophic lateral sclerosis (ALS) patients, as well as in the spinal cord and cranial motor nuclei in ALS transgenic mouse models [Anneser et al, 2004;Baron et al, 2005;Evans et al, 2014;Ferraiuolo et al, 2007;Poloni et al, 2000;Schiffer et al, 1996]. More importantly, increasing evidence suggests that reactive astrocytes contribute directly to the degeneration of motor circuits in ALS animal models by promoting non-cell autonomous mechanisms of motor neuron degeneration [Diaz-Amarilla et al, 2011;Ferraiuolo, 2014;Haidet-Phillips et al, 2011;Ouali Alami et al, 2018;Radford et al, 2015;Yamanaka and Komine, 2018].…”

Section: Introductionmentioning

confidence: 99%

Characterization of human iPSC-derived astrocytes with potential for disease modeling and drug discovery

Soubannier

Maussion

Chaineau

et al. 2019

Preprint

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ABSTRACTAstrocytes play a number of key functions in health and disease. Reactivation of astrocytes occurs in most, if not all, neurological diseases. Most current information on the mechanisms underlying astrogliosis derives from studies using rodent experimental systems, mainly because the ability to study human astrocytes under healthy and pathological conditions has been hampered by the difficulty in obtaining primary human astrocytes. Here we describe robust and reliable derivation of astrocytes from human induced pluripotent stem cells (iPSCs). Phenotypically characterized human iPSC-derived astrocytes exhibit typical traits of physiological astrocytes, including spontaneous and induced calcium transients. Moreover, human iPSC-derived astrocytes respond to stimulation with a pro-inflammatory combination of tumor necrosis factor alpha, interleukin 1-alpha, and complement component C1q by undergoing changes in gene expression patterns suggesting acquisition of a reactive astrocyte phenotype. Together, these findings provide evidence suggesting that human iPSC-derived astrocytes are a suitable experimental model system to study astrocyte function and reactivation in healthy and pathological conditions of the human nervous system.

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NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

Cited by 126 publications

References 65 publications

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Questions and (some) answers on reactive astrocytes

Characterization of human iPSC-derived astrocytes with potential for disease modeling and drug discovery

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