Cargando…

Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model

We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegener...

Descripción completa

Detalles Bibliográficos
Autores principales: Alsaad, Abdulaziz M. S., Ansari, Mushtaq A., Nadeem, Ahmed, Attia, Sabry M., Bakheet, Saleh A., Alomar, Hatun A., Ahmad, Sheikh F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455358/
https://www.ncbi.nlm.nih.gov/pubmed/37629172
http://dx.doi.org/10.3390/ijms241612991
_version_ 1785096432487759872
author Alsaad, Abdulaziz M. S.
Ansari, Mushtaq A.
Nadeem, Ahmed
Attia, Sabry M.
Bakheet, Saleh A.
Alomar, Hatun A.
Ahmad, Sheikh F.
author_facet Alsaad, Abdulaziz M. S.
Ansari, Mushtaq A.
Nadeem, Ahmed
Attia, Sabry M.
Bakheet, Saleh A.
Alomar, Hatun A.
Ahmad, Sheikh F.
author_sort Alsaad, Abdulaziz M. S.
collection PubMed
description We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage, and neurodegeneration. Over the past decade, pharmacological research into the H4R has gained significance in immune and inflammatory disorders. For this study, Swiss Jim Lambert EAE mice were treated with 4-MeH (30 mg/kg/day) via intraperitoneal administration from days 14 to 42, and the control group was treated with a vehicle. Subsequently, we evaluated the clinical scores. In addition, flow cytometry was employed to estimate the impact of 4-Methylhistamine (4-MeH) on NF-κB p65, GM-CSF, MCP-1, IL-6, and TNF-α within CD19(+) and CXCR5(+) spleen B cells. Additionally, we investigated the effect of 4-MeH on the mRNA expression levels of Nf-κB p65, Gmcsf, Mcp1, Il6, and Tnfα in the brain of mice using RT-PCR. Notably, the clinical scores of EAE mice treated with 4-MeH showed a significant increase compared with those treated with the vehicle. The percentage of cells expressing CD19(+)NF-κB p65(+), CXCR5(+)NF-κB p65(+), CD19(+)GM-CSF(+), CXCR5(+)GM-CSF(+), CD19(+)MCP-1(+), CXCR5(+)MCP-1(+), CD19(+)IL-6(+), CXCR5(+)IL-6(+), CD19(+)TNF-α(+), and CXCR5(+)TNF-α(+) exhibited was more pronounced in 4-MeH-treated EAE mice when compared to vehicle-treated EAE mice. Moreover, the administration of 4-MeH led to increased expression of NfκB p65, Gmcsf, Mcp1, Il6, and Tnfα mRNA in the brains of EAE mice. This means that the H4R agonist promotes pro-inflammatory mediators aggravating EAE symptoms. Our results indicate the harmful role of H4R agonists in the pathogenesis of MS in an EAE mouse model.
format Online
Article
Text
id pubmed-10455358
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-104553582023-08-26 Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model Alsaad, Abdulaziz M. S. Ansari, Mushtaq A. Nadeem, Ahmed Attia, Sabry M. Bakheet, Saleh A. Alomar, Hatun A. Ahmad, Sheikh F. Int J Mol Sci Article We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage, and neurodegeneration. Over the past decade, pharmacological research into the H4R has gained significance in immune and inflammatory disorders. For this study, Swiss Jim Lambert EAE mice were treated with 4-MeH (30 mg/kg/day) via intraperitoneal administration from days 14 to 42, and the control group was treated with a vehicle. Subsequently, we evaluated the clinical scores. In addition, flow cytometry was employed to estimate the impact of 4-Methylhistamine (4-MeH) on NF-κB p65, GM-CSF, MCP-1, IL-6, and TNF-α within CD19(+) and CXCR5(+) spleen B cells. Additionally, we investigated the effect of 4-MeH on the mRNA expression levels of Nf-κB p65, Gmcsf, Mcp1, Il6, and Tnfα in the brain of mice using RT-PCR. Notably, the clinical scores of EAE mice treated with 4-MeH showed a significant increase compared with those treated with the vehicle. The percentage of cells expressing CD19(+)NF-κB p65(+), CXCR5(+)NF-κB p65(+), CD19(+)GM-CSF(+), CXCR5(+)GM-CSF(+), CD19(+)MCP-1(+), CXCR5(+)MCP-1(+), CD19(+)IL-6(+), CXCR5(+)IL-6(+), CD19(+)TNF-α(+), and CXCR5(+)TNF-α(+) exhibited was more pronounced in 4-MeH-treated EAE mice when compared to vehicle-treated EAE mice. Moreover, the administration of 4-MeH led to increased expression of NfκB p65, Gmcsf, Mcp1, Il6, and Tnfα mRNA in the brains of EAE mice. This means that the H4R agonist promotes pro-inflammatory mediators aggravating EAE symptoms. Our results indicate the harmful role of H4R agonists in the pathogenesis of MS in an EAE mouse model. MDPI 2023-08-20 /pmc/articles/PMC10455358/ /pubmed/37629172 http://dx.doi.org/10.3390/ijms241612991 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alsaad, Abdulaziz M. S.
Ansari, Mushtaq A.
Nadeem, Ahmed
Attia, Sabry M.
Bakheet, Saleh A.
Alomar, Hatun A.
Ahmad, Sheikh F.
Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model
title Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model
title_full Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model
title_fullStr Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model
title_full_unstemmed Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model
title_short Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model
title_sort histamine h4 receptor agonist, 4-methylhistamine, aggravates disease progression and promotes pro-inflammatory signaling in b cells in an experimental autoimmune encephalomyelitis mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455358/
https://www.ncbi.nlm.nih.gov/pubmed/37629172
http://dx.doi.org/10.3390/ijms241612991
work_keys_str_mv AT alsaadabdulazizms histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel
AT ansarimushtaqa histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel
AT nadeemahmed histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel
AT attiasabrym histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel
AT bakheetsaleha histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel
AT alomarhatuna histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel
AT ahmadsheikhf histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel