Astrocytic NF-κB brings the best and worst out of microglia.

Abstract

News & Views23 July 2018free access Astrocytic NF-κB brings the best and worst out of microglia Nikolaos Dokalis Institute of Neuropathology, University Freiburg, Freiburg, Germany Search for more papers by this author Marco Prinz [email protected] orcid.org/0000-0002-0349-1955 Institute of Neuropathology, University Freiburg, Freiburg, Germany BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany Search for more papers by this author Nikolaos Dokalis Institute of Neuropathology, University Freiburg, Freiburg, Germany Search for more papers by this author Marco Prinz [email protected] orcid.org/0000-0002-0349-1955 Institute of Neuropathology, University Freiburg, Freiburg, Germany BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany Search for more papers by this author Author Information Nikolaos Dokalis1 and Marco Prinz1,2 1Institute of Neuropathology, University Freiburg, Freiburg, Germany 2BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany EMBO J (2018)37:e100130https://doi.org/10.15252/embj.2018100130 See also NO Alami et al (August 2018) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info The role of astrocytes and microglia in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) remains incompletely understood. In this issue of The EMBO Journal, Alami et al (2018) employ a sophisticated genetic system that allows precise temporal control of NF-κB activation in astrocytes to demonstrate that the timing of astrocyte activation is a key determinant of disease progression. Their results suggest that astrocyte activation drives microglia proliferation and that this can amplify not only the protective microglial effects in the presymptomatic phase of ALS, but also the detrimental microglial effects in the symptomatic phase. While neurons are the protagonists of the central nervous system (CNS), the supporting glial cells such as astrocytes and microglia have an essential role in maintaining CNS homeostasis. Glial cells are the first responders to central nervous system (CNS) insults, and their coordinated and highly regulated action is thought to be essential for successful recovery from local neural lesions. However, excessive or inappropriate activation of these cells can promote the progression of neurodegenerative diseases. We are just beginning to understand how the coordinated activity of different glial cell populations maintains CNS homeostasis (Rothhammer et al, 2018), and even less is known about how glial crosstalk influences the progression of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis is a terminal neurodegenerative disease characterized by progressive, non-cell autonomous death of CNS motor neurons and thereby loss of voluntary muscle control. In most patients, the cause of ALS is unknown, but 5–10% of cases are familial. Approximately one fifth of the familial ALS cases are linked to mutations in superoxide dismutase 1 (SOD1), a copper/zinc enzyme that normally detoxifies highly reactive superoxide radicals. The pathophysiology of ALS is complex and has been investigated in several animal models including the widespread SOD1(G39A) transgenic mouse. Evidence from these disease models and from ALS patients suggests that astrocytes and microglia are key players in the initiation and progression of disease. NF-κB is a highly conserved and broadly expressed transcription factor with a major role in regulating immunity, inflammation and cellular stress responses. NF-κB signaling has been strongly implicated to various CNS disorders, including neurodegeneration (Kaltschmidt et al, 1997), autoimmunity (Goldmann et al, 2013) and spinal cord injury (Bethea et al, 1998). Modulation of microglial NF-κB has been shown to affect the clinical manifestation of the disease (Frakes et al, 2014). Although activation of NF-κB in astrocytes has been observed during ALS (Haidet-Phillips et al, 2011), repression of the inhibitor of NF-κB kinase subunit beta IKK2 in astrocytes did not change the course of ALS (Frakes et al, 2014). However, astrocytic NF-κB signaling does play a role in other neurodegenerative disorders. For instance, it has been shown that astrocytic NF-κB activation plays a crucial pathogenic role during toxic (Raasch et al, 2011) and also neuroinflammatory (van Loo et al, 2006) demyelination in the CNS, regulating both the severity of myelin loss and concomitant neuronal damage. The current study by Alami et al (2018) demonstrates that astrocyte activation determines the course and severity of ALS by controlling microglia proliferation. In order to reveal the role of astrocyte activation in ALS, the authors employed a genetic model of tetracycline-regulated, astrocyte-specific IKK2/NF-κB activation in combination with the SOD1(G39A) mouse model. First, they demonstrated that NF-κB activation specifically in astrocytes leads to progressive gliosis and enhanced cell proliferation in the spinal cord. Astrocytic NF-κB activation also compromised the integrity of the blood–spinal cord barrier, which was accompanied by a progressive infiltration of lymphocytes. The proliferative cell fraction was mainly comprised of microglia cells. Interestingly, they observed phenotypic heterogeneity in the expanded microglia population that reflected resting and disease-associated cells, which can be differentiated on the basis of surface markers such as TMEM119, CD11c, and CD169. Furthermore, they observed that the switch from presymptomatic to the symptomatic disease phase was accompanied by a decrease in the proportion of resting microglia and an increase in the proportion of pro-inflammatory microglia. The authors then sought to determine how the timing of astrocyte NF-κB activation affects the course and severity of ALS. Although prolonged activation of the pathway (i.e., starting at postnatal day P25) had no net effect on overall survival time, it did change the course of disease progression. As compared to SOD1 mice, SOD1/IKK mice displayed delayed onset of the disease, but faster and more severe progression. Indeed, markers of disease progression such as misfolded SOD1, autophagy activation, and oxidative damage in the motor neurons were significantly reduced in mice with astrocytic NF-κB activation during the presymptomatic stage, but dramatically increased in the later stages. Given the differential impact of astrocyte NF-κB on microglial responses in early and late disease phases, Alami et al (2018) sought to determine how temporal dissociation of astrocyte NF-κB influences disease course. When astrocyte NF-κB was activated only in the early, presymptomatic phase of disease progression (P25-P80), mice displayed a delay in disease onset and longer survival. However, the mice did eventually succumb to disease after a delayed but markedly accelerated progression phase. In contrast, activation of astrocyte NF-κB after disease onset (i.e., from P80 onwards) reduced survival time. Despite the clinical manifestation, astrogliosis and microglia expansion and polarization were comparable at the late stages regardless of the time-point of the pathway activation. How does astrocyte NF-κB activation cause microglia proliferation? The authors rationalized that WNT proteins might mediate this effect, since they are secreted by astrocytes, induced by NF-κB, and are known to trigger proliferation of microglia. They observed that Wnt5a was significantly upregulated in astrocytes after activation of NF-κB pathway. Moreover, chemical inhibition of WNT release reduced microglia expansion. The authors then sought to influence disease outcome by controlling microglial proliferation in a therapeutic setting using full agonists and inverse agonists of the microglia-specific cannabinoid receptor 2 (CB2). Whereas full agonists of CB2 prevented microglial expansion and worsened disease progression, inverse agonists altered microglial morphological complexity, which was accompanied by a reduction in motor neuron degeneration. Collectively, these findings suggest that astrocyte Wnt5a promotes microglial proliferation and that pharmacological interventions directly promoting microglial proliferation during the early phases of ALS can reduce disease progression. Taken together, the study by Alami et al (2018) demonstrates that the timing of astrocyte activation crucially regulates neuroimmunological responses in ALS, affecting both disease onset and progression (Fig 1). Furthermore, this elegant study provides valuable insight into the cellular interplay of CNS-resident cells during ALS. Their results suggest that astrocyte NF-κB activation promotes microglial proliferation and that this can amplify the protective microglial effects in the presymptomatic phase of ALS, but also the detrimental microglial effects in the symptomatic phase. Although targeting microglial proliferation may represent a valid therapeutic strategy, the Alami et al (2018) study suggests that the timing of such interventions is critical. Specifically, promoting microglial expansion at late disease stages where microglia have already acquired a reactive, pro-inflammatory phenotype is likely to accelerate disease progression. Further studies deciphering the complexity of the neuroinflammatory environment and the interaction between both peripheral and resident cells (Prinz & Priller, 2017) will be required. Figure 1. The timing of astrocytic NF-κB activation determines microglia-dependent ALS pathologyDuring ALS progression, astrocytes (green) are suggested to regulate microglia (red) proliferation and shift from an anti-inflammatory to a pro-inflammatory phenotype contributing to the disease progression. Prolonged (P25 onwards) or early (P25–P80) astrocytic NF-κB activation extends the presymptomatic phase through Wnt5a-dependent microglia activation and expansion, but dramatically increases the severity of the symptomatic stage. In contrast, late activation of astrocytic NF-κB (P80 onwards) has no effect on disease onset, but rather exacerbates the disease progression. 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Cell wall remodelling due to acidification and expansin‐dependent loosening brings about a change in cell shape that has an important role in controlling the cell differentiation program. The cover shows the AHA2 proton pump expression domain in the Arabidopsis root tip (AHA2‐GFP in cyan). Cell walls are stained with propidium iodide (grey). From Elena Pacifici, Riccardo Di Mambro, Raffaele Dello Ioio, Paolo Costantino and Sabrina Sabatini: Acidic cell elongation drives cell differentiation in the Arabidopsis root. For detail see Article e99134. Scientific Image by Elena Pacifici. Volume 37Issue 1615 August 2018In this issue FiguresReferencesRelatedDetailsLoading ...