MyD88-mediated signaling is critical for the generation of seizure responses and cognitive impairment in a model of anti-N-methyl-D-aspartate receptor encephalitis.

Autor: Taraschenko O; Division of Epilepsy, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA., Fox HS; Division of Epilepsy, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA., Eldridge E; Division of Epilepsy, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA., Heliso P; Division of Epilepsy, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA., Al-Saleem F; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA., Dessain S; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA., Casale G; Division of Vascular Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA., Willcockson G; Nebraska Medicine Hospital, Omaha, Nebraska, USA., Anderson K; Division of Epilepsy, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA., Wang W; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, USA., Dingledine R; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, USA.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2024 May; Vol. 65 (5), pp. 1475-1487. Date of Electronic Publication: 2024 Mar 12.
DOI: 10.1111/epi.17931
Abstrakt: Objective: We previously demonstrated that interleukin-1 receptor-mediated immune activation contributes to seizure severity and memory loss in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. In the present study, we assessed the role of the myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in Toll-like receptor signaling, in the key phenotypic characteristics of anti-NMDAR encephalitis.
Methods: Monoclonal anti-NMDAR antibodies or control antibodies were infused into the lateral ventricle of MyD88 knockout mice (MyD88 -/- ) and control C56BL/6J mice (wild type [WT]) via osmotic minipumps for 2 weeks. Seizure responses were measured by electroencephalography. Upon completion of the infusion, the motor, anxiety, and memory functions of the mice were assessed. Astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adaptor molecule 1 [Iba-1]) activation and transcriptional activation for the principal inflammatory mediators involved in seizures were determined using immunohistochemistry and quantitative real-time polymerase chain reaction, respectively.
Results: As shown before, 80% of WT mice infused with anti-NMDAR antibodies (n = 10) developed seizures (median = 11, interquartile range [IQR] = 3-25 in 2 weeks). In contrast, only three of 14 MyD88 -/- mice (21.4%) had seizures (0, IQR = 0-.25, p = .01). The WT mice treated with antibodies also developed memory loss in the novel object recognition test, whereas such memory deficits were not apparent in MyD88 -/- mice treated with anti-NMDAR antibodies (p = .03) or control antibodies (p = .04). Furthermore, in contrast to the WT mice exposed to anti-NMDAR antibodies, the MyD88 -/- mice had a significantly lower induction of chemokine (C-C motif) ligand 2 (CCL2) in the hippocampus (p = .0001, Sidak tests). There were no significant changes in the expression of GFAP and Iba-1 in the MyD88 -/- mice treated with anti-NMDAR or control antibodies.
Significance: These findings suggest that MyD88-mediated signaling contributes to the seizure and memory phenotype in anti-NMDAR encephalitis and that CCL2 activation may participate in the expression of these features. The removal of MyD88 inflammation may be protective and therapeutically relevant.
(© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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