Thrombin-Induced Microglia Activation Modulated through Aryl Hydrocarbon Receptors.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Microglia*/metabolism ; Receptors, Aryl Hydrocarbon*/metabolism ; Thrombin*/pharmacology; Animals ; Mice ; Cell Line ; Macrophages/metabolism

Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin is related to the development of neurodegeneration disorders. In this study, we investigated the role of AhR in the development of thrombin-induced neurodegenerative processes, especially those concerning microglia. The primary culture of either wild type or AhR deleted microglia, as well as BV-2 cell lines, was used for an in vitro study. Hippocampal slice culture and animals with either wild type or with AhR deleted were used for the ex vivo and in vivo studies. Simulations of ligand protein docking showed a strong integration between the thrombin and AhR. In thrombin-triggered microglia cells, deleting AhR escalated both the NO release and iNOS expression. Such effects were abolished by the administration of the AhR agonist. In thrombin-activated microglia cells, downregulating AhR increased the following: vascular permeability, pro-inflammatory genetic expression, MMP-9 activity, and the ratio of M1/M2 phenotype. In the in vivo study, thrombin induced the activation of microglia and their volume, thereby contributing to the deterioration of neurobehavior. Deleting AhR furthermore aggravated the response in terms of impaired neurobehavior, increasing brain edema, aggregating microglia, and increasing neuronal death. In conclusion, thrombin caused the activation of microglia through increased vessel permeability, expression of inflammatory response, and phenotype of M1 microglia, as well the MMP activity. Deleting AhR augmented the above detrimental effects. These findings indicate that the modulation of AhR is essential for the regulation of thrombin-induced brain damages and that the AhR agonist may harbor the potentially therapeutic effect in thrombin-induced neurodegenerative disorder.

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TCVGH-PU1088103 Taichung Veterans General Hospital; TCVGH-1117303C Taichung Veterans General Hospital; TCVGH-1117303D Taichung Veterans General Hospital; MOST 108-2314-B-010-024 National Science and Technology Council

Keywords: aryl hydrocarbon receptor; inflammation; microglia; neurodegenerative disorder; thrombin

0 (Receptors, Aryl Hydrocarbon)
EC 3.4.21.5 (Thrombin)

Date Created: 20230729 Date Completed: 20230817 Latest Revision: 20230817

20230817

PMC10380349

10.3390/ijms241411416

37511175