Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy

Abstract

Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.

Association of High Plasma Levels of Serpin E1, IGFBP2, and CCL5 With Refractory Epilepsy in Children by Cytokine Profiling

“…A recent study showed that the expression level of Serpin E1' family member, SerpinA3N, in the hippocampus of temporal lobe epilepsy mice induced by KA was significantly increased, and it promoted neuroinflammation and seizure by activating NF-κB signaling pathway, suggesting that Serpin family is closely related to epilepsy. 30 Therefore, it is worthy to further explore if initial seizures-induced inflammation elicits elevation of blood Serpin E1 and if its long persistence is implicated in the development or maintenance of DRE.…”

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

“…Furthermore, Serpina3n was reported to be primarily dysregulated in astrocytes in a kainic acid (KA)-induced temporal lobe epilepsy (TLE) mouse model; its overexpression promoted, whereas its KD attenuated pro-inflammatory cytokine expression and astrocyte reactivity in the hippocampus. 64 Taken together, these animal data prompt us to hypothesise that astrocytederived Serpina3n/SERPINA3 plays a strong pro-inflammatory role in neurological diseases/injuries; its experimental overexpression in astrocytes is sufficient to initiate inflammatory responses even in the homeostatic brain.…”

“…Serpina3n was reported to promote neuronal survival through inhibiting granzyme B 27,53 or clusterin 54 in ischaemic brain injury, whereas it promoted neuronal survival in traumatic brain injury by inhibiting leukocyte elastase 55 or matrix metalloproteinase 2 (MMP2), 61 but not granzyme B. In sharp contrast, astrocytederived Serpina3n was shown to aggravate neuronal injury and death in chemical-induced neurotoxic injury 60 and epileptic injury 64 presumably through promoting neuroinflammation as discussed above. These seemingly contradictory data suggest that the role of Ser-pina3n in neuronal death/survival depends on its cellular sources and/or injury types.…”

Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus

“…After washing, the tissues were reacted with Cy3-conjugated immunoglobulin G (IgG) and fluorescein isothiocyanate (FITC)-conjugated IgG antibody for 2 h. The sections were observed using a confocal microscope (LSM700, Carl Zeiss, Thornwood, NY, USA). Sirt3-GFAP double-positive cells were counted in the CA1 subfield of the hippocampus of patients with TLE with HS to analyze the changes of Sirt3 expression within reactive astrocytes (Liu et al, 2023).…”