Detrimental Effects of HMGB-1 Require Microglial-Astroglial Interaction: Implications for the Status Epilepticus -Induced Neuroinflammation

Abstract

Temporal Lobe Epilepsy (TLE) is the most common form of human epilepsy and available treatments with antiepileptic drugs are not disease-modifying therapies. The neuroinflammation, neuronal death and exacerbated plasticity that occur during the silent period, following the initial precipitating event (IPE), seem to be crucial for epileptogenesis. Damage Associated Molecular Patterns (DAMP) such as HMGB-1, are released early during this period concomitantly with a phenomenon of reactive gliosis and neurodegeneration. Here, using a combination of primary neuronal and glial cell cultures, we show that exposure to HMGB-1 induces dendrite loss and neurodegeneration in a glial-dependent manner. In glial cells, loss of function studies showed that HMGB-1 exposure induces NF-κB activation by engaging a signaling pathway that involves TLR2, TLR4, and RAGE. In the absence of glial cells, HMGB-1 failed to induce neurodegeneration of primary cultured cortical neurons. Moreover, purified astrocytes were unable to fully respond to HMGB-1 with NF-κB activation and required microglial cooperation. In agreement, in vivo HMGB-1 blockage with glycyrrhizin, immediately after pilocarpine-induced status epilepticus (SE), reduced neuronal degeneration, reactive astrogliosis and microgliosis in the long term. We conclude that microglial-astroglial cooperation is required for astrocytes to respond to HMGB-1 and to induce neurodegeneration. Disruption of this HMGB-1 mediated signaling pathway shows beneficial effects by reducing neuroinflammation and neurodegeneration after SE. Thus, early treatment strategies during the latency period aimed at blocking downstream signaling pathways activated by HMGB-1 are likely to have a significant effect in the neuroinflammation and neurodegeneration that are proposed as key factors in epileptogenesis.

Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

“…Moreover, overexpression of a plethora of proinflammatory cytokines was observed in the brain of SARS-CoV-infected mice, most notably IL-6, interferon (IFN)-γ, chemokine (C-C motif) ligand (CCL)-2, and CCL12 ( Glass et al., 2004 ; McCray et al., 2007 ; Tseng et al., 2007 ) and also in cases reported in humans ( Xu et al., 2005 ). We now know that astrocytes are highly sensitive to increased proinflammatory mediators and that this stimulus induce a proinflammatory gene expression program in astrocytes ( Liddelow and Barres, 2017 ; Rosciszewski et al., 2019 ; Verkhratsky et al., 2019 ).…”

“…Reactive gliosis is a fine graded and highly conserved mechanism of astroglial response to injury, and, in general terms, it is supposed to be aimed to improve neuronal survival, to restore BBB, and to isolate the injured area by providing glial scar formation ( Sofroniew and Vinters, 2010 ; Anderson et al., 2016 ; Verkhratsky et al., 2019 ). However, under certain not yet completely defined circumstances, but probably involving proinflammatory microglial activation and toll-like/NF-κB/STAT3-dependent pathways, astrocytes may engage into a proinflammatory gene expression program also called maladaptive reactive astrogliosis that transforms astrocytes into proinflammatory and proneurodegenerative cells ( Pekny et al., 2016 ; Liddelow et al., 2017 ; Rosciszewski et al., 2018 , 2019 ; Zorec et al., 2019 ). Transcriptomic analyses of reactive astrocytes have also identified this spectrum of possible activation profiles ranging between two extreme phenotypes that were simplistically defined as the proinflammatory proneurodegenerative A1 phenotype and the proneuronal survival immunomodulatory A2 phenotype, but these studies also showed mixed reactive profiles characterized by the expression of PAN-reactive genes ( Hamby et al., 2012 ; Zamanian et al., 2012 ; Anderson et al., 2016 ; Burda and Sofroniew, 2017 ; Liddelow and Barres, 2017 ; Liddelow et al., 2017 ; Clarke et al., 2018 ).…”

“…Transcriptomic analyses of reactive astrocytes have also identified this spectrum of possible activation profiles ranging between two extreme phenotypes that were simplistically defined as the proinflammatory proneurodegenerative A1 phenotype and the proneuronal survival immunomodulatory A2 phenotype, but these studies also showed mixed reactive profiles characterized by the expression of PAN-reactive genes ( Hamby et al., 2012 ; Zamanian et al., 2012 ; Anderson et al., 2016 ; Burda and Sofroniew, 2017 ; Liddelow and Barres, 2017 ; Liddelow et al., 2017 ; Clarke et al., 2018 ). Intensive research from our group and others has shown that astroglial engagement in the proinflammatory-neurodegenerative gene expression program is facilitated by astroglial exposure to pathogen-associated molecular patterns (PAMP), damage-associated molecular patterns (DAMP), and to microglial-derived proinflammatory cytokines ( Rothhammer et al., 2016 ; Liddelow et al., 2017 ; Rosciszewski et al., 2018 , 2019 ). It is also proposed that persisting reactive gliosis, as shown in neurodegenerative diseases, as well as infectious agents reaching the CNS, facilitate the proinflammatory program in reactive astrocytes (reviewed in Pekny et al., 2016 ; Zorec et al., 2019 ).…”

Boosting Antioxidant Self-defenses by Grafting Astrocytes Rejuvenates the Aged Microenvironment and Mitigates Nigrostriatal Toxicity in Parkinsonian Brain via an Nrf2-Driven Wnt/β-Catenin Prosurvival Axis

“…In fact, microglial cells show age-dependent and regionspecific changes in morphology such as structural deterioration or dystrophy, decreased expression of growth/neurotrophic factors, and an impaired phagocytic activity in the face of increased marker expression and upregulation of pro-inflammatory molecules (see Niraula et al, 2017, and references herein), all of which are associated to a gradual loss of As and microglia neuroprotective capacity. Reportedly, microglia switch to a so-called ''primed'' status, endowed with a strong neurotoxic, pro-inflammatory M1 phenotype with harmful consequences for As-neuron interactions (Miller and Streit, 2007;Liddelow et al, 2017;Rosciszewski et al, 2018Rosciszewski et al, , 2019 and DAergic neuron survival upon injury (L'Episcopo et al, 2011a(L'Episcopo et al, ,b,c, 2018a.…”

Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms

“…In light of current findings, it is proposed that stress-induced increases in glucocorticoids activates glucocorticoid receptors and subsequently increases HMGB1 release from CNS astrocyte. Extracellular HMGB1 interact with TLR2, TLR4, and RAGE which express in astrocyte and microglia [67,68] to induce innate immunity activation [69]. Astrocyte-derived HMGB1 could then be involved in neuroinflammatory processes which, in turn, mediate psychiatric disorders such as MDD.…”