A potent and selective CXCR2 antagonist improves neuroimmune dysregulation through the inhibition of NF-κB and notch inflammatory signaling in the BTBR mouse model of autism

Autism comprises a broad range of neurodevelopmental disorders characterized by social communication deficits and repetitive and stereotyped behaviors. Chemokine receptor CXCR2 is expressed on neurons and is upregulated in neurological disorders. BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism tha...

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Published in:Journal of neuroimmunology 2023-04, Vol.377, p.578069-578069, Article 578069
Main Authors: Alomar, Hatun A., Ansari, Mushtaq A., Nadeem, Ahmed, Attia, Sabry M., Bakheet, Saleh A., Al-Mazroua, Haneen A., Hussein, Marwa H., Alqarni, Saleh A., Ahmad, Sheikh F.
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - therapeutic use
Autism
Autistic Disorder - drug therapy
BTBR T+ Itpr3tf/J mice
CXCR2 antagonist
Disease Models, Animal
Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use
Inflammatory mediators
Interleukin-2
Interleukin-6
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
NF-kappa B - metabolism
NF-κB/notch signaling
RNA, Messenger
Transforming Growth Factor beta1
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Summary:Autism comprises a broad range of neurodevelopmental disorders characterized by social communication deficits and repetitive and stereotyped behaviors. Chemokine receptor CXCR2 is expressed on neurons and is upregulated in neurological disorders. BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism that shows the core features of ASD. Here, we studied the anti-inflammatory effect of a potent and selective CXCR2 antagonist SB332235 in the BTBR mice. The CXCR2 antagonist represents a promising therapeutic agent for several neuroinflammatory disorders. In this study, we investigated the effects of SB332235 administration on NF-κB-, Notch-1-, Notch-3-, GM-CSF-, MCP-1-, IL-6-, and IL-2- and TGF-β1-expressing CD40+ cells in BTBR and C57BL/6 (C57) mice in the spleen cells by flow cytometry. We further assessed the effect of SB332235 treatment on NF-κB, Notch-1, GM-CSF, MCP-1, IL-6, and IL-2 mRNA expression levels in the brain tissue by RT-PCR. We also explored the effect of SB332235 administration on NF-κB, GM-CSF, IL-6, and TGF-β1 protein expression levels in the brain tissue by western blotting. The SB332235-treated BTBR mice significantly decreases in CD40 + NF-κB+, CD40 + Notch-1+, CD40 + Notch-3+, CD40 + GM-CSF+, CD40 + MCP-1+, CD40 + IL-6+, and CD40 + IL-2+, and increases in CD40 + TGF-β1+ in the spleen cells. Our results further demonstrated that BTBR mice treated with SB332235 effectively decreased NF-κB, Notch-1, GM-CSF, MCP-1, IL-6, and IL-2, increasing TGF-β1 mRNA and protein expression levels in the brain tissue. In conclusion, these results indicate that SB332235 elicits an anti-inflammatory response by downregulating the inflammatory mediators and NF-κB/Notch inflammatory signaling in BTBR mice. This could represent a promising novel therapeutic target for autism treatment. •We study the effect of CXCR2 antagonist in the model of BTBR mice.•SB332235 treatment downregulates inflammatory mediators in BTBR mice.•SB332235 decreases NF-κB/Notch-producing CD40+ cells in BTBR mice.•SB332235 treatment downregulates GM-CSF and MCP expression levels in BTBR mice.•SB332235 could be a potential therapeutic for the treatment of ASD.
ISSN:0165-5728
1872-8421
DOI:10.1016/j.jneuroim.2023.578069