Cadmium exposure exacerbates immunological abnormalities in a BTBR T(+) Itpr3(tf)/J autistic mouse model by upregulating inflammatory mediators in CD45R-expressing cells.

Albekairi TH ，Alanazi MM ，Ansari MA ，Nadeem A ，Attia SM ，Bakheet SA ，Al-Mazroua HA ，Aldossari AA ，Almanaa TN ，Alwetaid MY ，Alqinyah M ，Alnefaie HO ，Ahmad SF ... -  《-》

Lead (Pb) exposure exacerbates behavioral and immune abnormalities by upregulating Th17 and NF-κB-related signaling in BTBR T(+) Itpr3(tf)/J autistic mouse model.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that are characterized by abnormal social interaction impairments in communication and repetitive and restricted activities or interests. Even though the exact etiology of ASD remains unknown. Lead (Pb) is a toxin known to harm many organs in the body, it is one of the most ubiquitous metal exposures which is associated with neurological deficits. Previous studies have shown that the exposure to Pb may play a role in ASD. BTBR T+ Itpr3tf/J (BTBR) mouse model is commonly used as a preclinical model for ASD. In this study, we investigated the effects of Pb exposure on sociability, self-grooming and marble burying behaviors tests in BTBR mice. We further examined the effects of Pb on IL-17A- RORγT-, STAT3-, NF-κB p65-, iNOS-, TLR-2- and TLR-4-producing CD45+ cells in spleen using flow cytometry. We also explored the effects of Pb on IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA expression in the brain tissue using RT-PCR analysis. Our results demonstrated that Pb exposure substantially increased repetitive behavior, marble burying and decrease social interactions in BTBR mice. In addition, in spleen cells, Pb exposure exaggerated CD45+IL-17A+, CD45+RORγT+, CD45+STAT3+, CD45+NF-κB p65+, CD45+iNOS+, CD45+TLR-2+ and CD45+TLR-4+ in BTBR mice. We also found that Pb significantly increased IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA in the brain tissue. Therefore, Pb exposure exacerbates behavioral and neuroimmune function in BTBR mice, suggesting a potentially strong role for Pb in ASD.

Almutairi MM ，Nadeem A ，Ansari MA ，Bakheet SA ，Attia SM ，Albekairi TH ，Alhosaini K ，Algahtani M ，Alsaad AMS ，Al-Mazroua HA ，Ahmad SF ... -  《-》

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 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.

Alomar HA ，Ansari MA ，Nadeem A ，Attia SM ，Bakheet SA ，Al-Mazroua HA ，Hussein MH ，Alqarni SA ，Ahmad SF ... -  《-》

Aflatoxin B(1) exposure deteriorates immune abnormalities in a BTBR T(+) Itpr3(tf)/J mouse model of autism by increasing inflammatory mediators' production in CD19-expressing cells.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficiencies in communication, repetitive and stereotyped behavioral patterns, and difficulties in reciprocal social engagement. The presence of immunological dysfunction in ASD has been well established. Aflatoxin B1 (AFB1) is a prevalent mycotoxin found in food and feed, causing immune toxicity and hepatotoxicity. AFB1 is significantly elevated in several regions around the globe. Existing research indicates that prolonged exposure to AFB1 results in neurological problems. The BTBR T+ Itpr3tf/J (BTBR) mice, which were used as an autism model, exhibit the primary behavioral traits that define ASD, such as repeated, stereotyped behaviors and impaired social interactions. The main objective of this work was to assess the toxic impact of AFB1 in BTBR mice. This work aimed to examine the effects of AFB1 on the expression of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 by CD19+ B cells in the spleen of the BTBR using flow cytometry. We also verified the impact of AFB1 exposure on the mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain of BTBR mice using real-time PCR. The findings of our study showed that the mice treated with AFB1 in the BTBR group exhibited a substantial increase in the presence of CD19+Notch-1+, CD19+IL-6+, CD19+MCP-1+, CD19+iNOS+, CD19+GM-CSF+, and CD19+NF-κB p65+ compared to the mice in the BTBR group that were treated with saline. Our findings also confirmed that administering AFB1 to BTBR mice leads to elevated mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain, in comparison to BTBR mice treated with saline. The data highlight that exposure to AFB1 worsens immunological abnormalities by increasing the expression of inflammatory mediators in BTBR mice.

Almanaa TN ，Alwetaid MY ，Bakheet SA ，Attia SM ，Ansari MA ，Nadeem A ，Ahmad SF ... -  《-》

Methylmercury chloride exposure aggravates proinflammatory mediators and Notch-1 signaling in CD14(+) and CD40(+) cells and is associated with imbalance of neuroimmune function in BTBR T(+) Itpr3tf/J mice.

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviors. A key role for immune dysfunction has been suggested in ASD. Recent studies have indicated that inflammatory mediators and Notch-1 signaling may contribute to the development of ASD. Methylmercury chloride (MeHgCl) is an environmental pollutant that primarily affects the central nervous system, causing neurological alterations. Its effects on immunological responses have not been fully investigated in ASD. In this study, we examined the influence of MeHgCl exposure on inflammatory mediators and Notch-1 signaling in BTBR T+ Itpr3tf/J (BTBR) mice, a model of ASD. We examined the effects of MeHgCl on the IL-6-, GM-CSF-, NF-κB p65-, Notch-1-, and IL-27-producing CD14+ and CD40+ cells in the spleen. We assessed the effect of MeHgCl on IL-6, GM-CSF, NF-κB p65, Notch-1, and IL-27 mRNA levels in brain tissue. We also measured IL-6, GM-CSF, and NF-κB p65 protein expression levels in brain tissue. MeHgCl exposure of BTBR mice significantly increased IL-6-, GM-CSF-, NF-κB p65-, and Notch-1-, and decreased IL-27-producing CD14+, and CD40+ cells in the spleen. MeHgCl exposure of BTBR mice upregulated IL-6, GM-CSF, NF-κB p65, and Notch-1, and decreased IL-27 mRNA expression levels in brain tissue. Moreover, MeHgCl resulted in elevated expression of the IL-6, GM-CSF, and NF-κB p65 proteins in brain tissue. Taken together, these results indicate that MeHgCl exposure aggravates proinflammatory mediators and Notch-1 signaling which are associated with imbalance of neuroimmune function in BTBR mice.

Ahmad SF ，Bakheet SA ，Ansari MA ，Nadeem A ，Alobaidi AF ，Attia SM ，Alhamed AS ，Aldossari AA ，Mahmoud MA ... -  《-》