Reactive Glia Inflammatory Signaling Pathways and Epilepsy

Abstract

Neuroinflammation and epilepsy are interconnected. Brain inflammation promotes neuronal hyper-excitability and seizures, and dysregulation in the glia immune-inflammatory function is a common factor that predisposes or contributes to the generation of seizures. At the same time, acute seizures upregulate the production of pro-inflammatory cytokines in microglia and astrocytes, triggering a downstream cascade of inflammatory mediators. Therefore, epileptic seizures and inflammatory mediators form a vicious positive feedback loop, reinforcing each other. In this work, we have reviewed the main glial signaling pathways involved in neuroinflammation, how they are affected in epileptic conditions, and the therapeutic opportunities they offer to prevent these disorders.

Keywords: epilepsy; inflammation; microglia; reactive astrocytes; signaling pathways.

Figure 1

Toll-like receptors (TLRs) signaling pathway. Schematic view of the components of the TLRs signaling pathways. See text for details. TLR4, RAGE, and IL-1R1 are mainly located at the plasma membrane, whereas TLR3 is located in intracellular vesicles. Components of the pathway that are increased in epilepsy are in blue. Therapeutic strategies to prevent the pathway are in red. NAC+SFN: N-acetyl-cysteine plus sulforaphane; α-HMGB1: anti-high mobility group box 1 monoclonal antibody; α-IL-1β: anti-interleukin-1β monoclonal antibody. Pointed arrows indicate direction of the signaling pathway. Blunt arrows indicate inhibition.

Figure 2

Canonical and non-canonical inflammasome pathways. The canonical pathway is a two-step process: first, the NF-kB pathway activates the expression of pro-IL-1β and pro-IL-18; then activation of the inflammasome (e.g., NLRP3) is required (e.g., by K+ efflux or by ROS) to activate caspase1. In the non-canonical pathway, the activation of caspase11 by intracellular inducers leads to the generation of Gasdermin-Nterm (GSDMD-Nterm), which translocates to the membrane and creates pores that allow the efflux of K+ and the release of mature cytokines. See text for details. Components of the pathway that are increased in epilepsy are in blue. Caspase 11 (i), inactive form. Pointed arrows define the direction of the signaling pathways. Wide grey arrow indicate transcriptional regulation.

Figure 3

Tumor necrosis factor α (TNFα)/TNFR1 signaling pathway. (A) Schematic view of the components of the signaling pathway. See text for details. Components of the pathway that are increased in epilepsy are in blue. Therapeutic strategies to prevent the pathway are in red. (B) TNFα enhances neuronal glutamatergic transmission: On the one hand, it increases the levels of glutamate (Glu), and on the other hand, it enhances the activity of postsynaptic glutamate receptors. See the text for details. Pointed arrows indicate direction of the signaling pathway. Blunt arrows indicate inhibition.

Figure 4

(A) Interleukin (IL)-6/Grp130-JAK-STAT signaling pathway. Schematic view of the components of the signaling pathway. View text for details. Components of the pathway that are increased in epilepsy are in blue. Therapeutic strategies to prevent the pathway are in red. (B) Albumin-TGFβ/TGFβ-RI/II signaling pathway. Schematic view of the components of the pathway. See text for details. Components of the pathway that are increased in epilepsy are in blue. Therapeutic strategies to prevent the pathway are in red. Pointed arrows indicate direction of the signaling pathway. Blunt arrows indicate inhibition.

Figure 5

(A) Chemokine signaling pathway. CCR2, CCR5, and CXCR3 belong to the group of G-protein coupled receptors (GPCRs). Schematic view of the components of the signaling pathway; see text for details. Components of the pathway that are increased in epilepsy are in blue. Therapeutic strategies to prevent the pathway are in red. (B) Lcn2/LCN2R signaling pathway. Schematic view of the components of the pathway. See text for details. Components of the pathway that are increased in epilepsy are in blue. Pointed arrows indicate direction of the signaling pathway. Blunt arrows indicate inhibition.

Figure 6

Functional relationship between GFAP+ (glial fibrillary acidic protein) reactive astrocytes and IBA+ (ionized calcium-binding adapter molecule) activated microglia. Reactive astrocytes produce critical components that activate microglia (e.g., CXCL10, HMGB1, Lcn2, C3, etc.). These components are recognized by specific microglial receptors (CXCR3, TLR4/RAGE, LCN2R, C3aR, respectively) that trigger signaling cascades leading to microglia activation. Microglia can also get activated by increases in the levels of ATP, reactive oxygen species (ROS), or glutamate in the medium. Activated microglia produces IL-1α, TNFα, and C1q, which transform resting astrocytes into type A1 reactive astrocytes. Therapeutic strategies to prevent this action are in red. In addition, activated microglia participates in the phagocytosis of neurons using specific receptors (e.g., TREM2—triggering receptor expressed on myeloid cells 2) that recognize specific “eat-me” signals. As a consequence of astrocyte and microglia reactivity, critical mediators in glial physiology are altered, leading to seizures. Pointed arrows indicate direction of the signaling pathway. Blunt arrows indicate inhibition.