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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/16/12991 |
| _version_ | 1797584431468249088 |
|---|---|
| author | Abdulaziz M. S. Alsaad Mushtaq A. Ansari Ahmed Nadeem Sabry M. Attia Saleh A. Bakheet Hatun A. Alomar Sheikh F. Ahmad |
| author_facet | Abdulaziz M. S. Alsaad Mushtaq A. Ansari Ahmed Nadeem Sabry M. Attia Saleh A. Bakheet Hatun A. Alomar Sheikh F. Ahmad |
| author_sort | Abdulaziz M. S. Alsaad |
| collection | DOAJ |
| 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<sup>+</sup> and CXCR5<sup>+</sup> 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<sup>+</sup>NF-κB p65<sup>+</sup>, CXCR5<sup>+</sup>NF-κB p65<sup>+</sup>, CD19<sup>+</sup>GM-CSF<sup>+</sup>, CXCR5<sup>+</sup>GM-CSF<sup>+</sup>, CD19<sup>+</sup>MCP-1<sup>+</sup>, CXCR5<sup>+</sup>MCP-1<sup>+</sup>, CD19<sup>+</sup>IL-6<sup>+</sup>, CXCR5<sup>+</sup>IL-6<sup>+</sup>, CD19<sup>+</sup>TNF-α<sup>+</sup>, and CXCR5<sup>+</sup>TNF-α<sup>+</sup> 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. |
| first_indexed | 2024-03-10T23:51:41Z |
| format | Article |
| id | doaj.art-aaa6c3ddcfc44388af99f5b50c5d67c6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:51:41Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-aaa6c3ddcfc44388af99f5b50c5d67c62023-11-19T01:33:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161299110.3390/ijms241612991Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse ModelAbdulaziz M. S. Alsaad0Mushtaq A. Ansari1Ahmed Nadeem2Sabry M. Attia3Saleh A. Bakheet4Hatun A. Alomar5Sheikh F. Ahmad6Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaWe 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<sup>+</sup> and CXCR5<sup>+</sup> 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<sup>+</sup>NF-κB p65<sup>+</sup>, CXCR5<sup>+</sup>NF-κB p65<sup>+</sup>, CD19<sup>+</sup>GM-CSF<sup>+</sup>, CXCR5<sup>+</sup>GM-CSF<sup>+</sup>, CD19<sup>+</sup>MCP-1<sup>+</sup>, CXCR5<sup>+</sup>MCP-1<sup>+</sup>, CD19<sup>+</sup>IL-6<sup>+</sup>, CXCR5<sup>+</sup>IL-6<sup>+</sup>, CD19<sup>+</sup>TNF-α<sup>+</sup>, and CXCR5<sup>+</sup>TNF-α<sup>+</sup> 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.https://www.mdpi.com/1422-0067/24/16/12991histamine H4 receptor agonistEAEmultiple sclerosisinflammatory mediatorsflow cytometry |
| spellingShingle | Abdulaziz M. S. Alsaad Mushtaq A. Ansari Ahmed Nadeem Sabry M. Attia Saleh A. Bakheet Hatun A. Alomar Sheikh F. Ahmad Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model International Journal of Molecular Sciences histamine H4 receptor agonist EAE multiple sclerosis inflammatory mediators flow cytometry |
| 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 | histamine H4 receptor agonist EAE multiple sclerosis inflammatory mediators flow cytometry |
| url | https://www.mdpi.com/1422-0067/24/16/12991 |
| work_keys_str_mv | AT abdulazizmsalsaad histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel AT mushtaqaansari histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel AT ahmednadeem histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel AT sabrymattia histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel AT salehabakheet histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel AT hatunaalomar histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel AT sheikhfahmad histamineh4receptoragonist4methylhistamineaggravatesdiseaseprogressionandpromotesproinflammatorysignalinginbcellsinanexperimentalautoimmuneencephalomyelitismousemodel |