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Sneaky Entry of IFNγ Through Arsenic-Induced Leaky Blood–Brain Barrier Reduces CD200 Expression by Microglial pro-Inflammatory Cytokine

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A Correction to this article was published on 02 August 2018

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Abstract

Recent studies showed that neuronal surface protein CD200 plays a key role in the regulation of neuroinflammation. Previously, we showed that arsenic (0.38 mg/kg body weight) exposure induces microglial activation and consequently IL-6/TNF-α secretion. This result indicated the possibility of alteration in the expression of CD200. Therefore, the present study was focused on checking arsenic-induced alteration in CD200 expression and revealing the underlying mechanism. Male BALB/c mice were exposed to arsenic (vehicle, 0.038 and 0.38 mg/kg body weight) for 60 days, and the expression level of CD200 was found to be decreased which was rescued by minocycline (33 mg/kg body weight) co-administration. Higher CD68 staining, increased level of IL-6/TNF-α, as well as higher level of IFNγ, were observed in in vivo arsenic-exposed groups. Interestingly, in vitro arsenic exposure could not increase IL-6/TNF-α level in the culture supernatant, whereas, supplementation of IFNγ could mimic the in vivo results. However, arsenic could not induce IFNγ production from brain endothelial cells, microglia, and astrocytes, thereby suggesting the entry of IFNγ through the impaired blood–brain barrier. Evans blue fluorescence in the brain confirms altered blood–brain barrier permeability although no changes were observed in the expression level of tight junction proteins (claudin-5 and occludin). Finally, intracerebral injection of anti-IFNγ neutralizing antibody in arsenic-exposed brain reduced microglia activation (IL-6 and TNF-α and CD68 expression) and subsequently rescued CD200 level. Taken together, the study showed that arsenic-mediated compromised blood–brain barrier is a major driving force to induce microglial IL-6 and TNF-α production through serum IFNγ leading to CD200 downregulation.

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  • 02 August 2018

    The original version of this article unfortunately contained mistake on Fig. 3A.

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Funding

This work was supported by CSIR-12th 5-year network project, INDEPTH (BSC001) (CSIR, Council of Scientific and Industrial Research). V.S and J.M were supported by CSIR Senior Research Fellowship. R.G, J.D, and J.A.A were supported by UGC-Senior Research Fellowship, respectively. S.K was supported by CSIR Junior Research Fellowship. The CSIR-IITR manuscript number is 3528.

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Authors and Affiliations

  1. Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group, and Nanotherapeutics & Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, P.O. Box No. 80, Lucknow, Uttar Pradesh, 226001, India

    Vikas Singh, Shaivya Kushwaha, Ruchi Gera, Jamal Ahmad Ansari & Debabrata Ghosh

  2. Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR campus, Lucknow, 226001, India

    Vikas Singh, Shaivya Kushwaha, Ruchi Gera, Jamal Ahmad Ansari, Satyakam Patnaik & Debabrata Ghosh

  3. Developmental toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, 226001, India

    Juhi Mishra

  4. Genotoxicity Lab, CSIR-Central Drug Research Institute, Uttar Pradesh, Lucknow, 226031, India

    Jayant Dewangan

  5. Water Analysis Laboratory, Nanotherapeutics and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, 226001, India

    Satyakam Patnaik

Authors
  1. Vikas Singh
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  2. Shaivya Kushwaha
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  3. Ruchi Gera
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  4. Jamal Ahmad Ansari
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  8. Debabrata Ghosh
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Correspondence to Debabrata Ghosh.

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Singh, V., Kushwaha, S., Gera, R. et al. Sneaky Entry of IFNγ Through Arsenic-Induced Leaky Blood–Brain Barrier Reduces CD200 Expression by Microglial pro-Inflammatory Cytokine. Mol Neurobiol 56, 1488–1499 (2019). https://doi.org/10.1007/s12035-018-1155-0

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  • DOI: https://doi.org/10.1007/s12035-018-1155-0

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