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Interleukin 4 Reduces Brain Hyperexcitability after Traumatic Injury by Downregulating TNF-α, Upregulating IL-10/TGF-β, and Potential Directing Macrophage/Microglia to the M2 Anti-inflammatory Phenotype

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Abstract—

Macrophage/microglia are activated after Traumatic brain injury (TBI), transform to inflammatory phenotype (M1) and trigger neuroinflammation, which provokes epileptogenesis. Interleukin-4 (IL-4) is a well-known drive of macrophage/microglia to the anti-inflammatory phenotype (M2). We tested effect of IL-4 on speed of epileptogenesis, brain expression of inflammatory and anti-inflammatory cytokines, and lesion size in TBI-injured male rats. Rats underwent TBI by Controlled Cortical Impact. Then 100 ng IL-4 was injected into cerebral ventricles. One day after TBI, pentylenetetrazole (PTZ) kindling started and development of generalized seizures was recorded. The lesion size, cell survival rate, TNF-α, TGF-β, IL-10, and Arginase1 (Arg1) was measured in the brain 6 h, 12 h, 24 h, 48 h, and 5 days after TBI. Astrocytes and macrophage/microglia activation/polarization was assessed by GFAP/Arg1 and Iba1/Arg1 immunostaining. TBI-injured rats were kindled by 50% less PTZ injections than control and sham-operated rats. IL-4 did not change kindling rate in sham-operated rats but inhibited acceleration of kindling rate in the TBI-injured rats. IL-4 decreased damage volume and number of destroyed neurons. IL-4 stopped TNF-α whereas upregulated TGF-β, IL-10, and Arg1 expressions. Iba1/Arg1 positive macrophage/microglia was notably increased 48 h after IL-4 administration. IL-4 suppresses TBI-induced acceleration of epileptogenesis in rats by directing TBI neuroinflammation toward an anti-inflammatory tone and inhibition of cell death.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

Research reported in this publication was supported by Elite Researcher Grant Committee under award number [943697] from the National Institute for Medical Research Development (NIMAD), Tehran, Iran.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Pasteur Institute of Iran , Tehran, Iran

    Mozhdeh Radpour, Bahar Khoshkroodian, Tara Asgari, Hamid Gholami Pourbadie & Mohammad Sayyah

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  1. Mozhdeh Radpour
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  2. Bahar Khoshkroodian
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  3. Tara Asgari
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  4. Hamid Gholami Pourbadie
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  5. Mohammad Sayyah
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Contributions

Acquisition of data, statistical analysis, data presentation: M Radpour, B Khoshkroodian, T Asgari; Experimental design, statistical analysis, data interpretation: HG Pourbadie; Study concept and design, obtained funding, administrative, technical, and material support, study supervision, analysis and interpretation of data, drafting the manuscript: M Sayyah.

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Correspondence to Mohammad Sayyah.

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All animal experiments were carried out in accordance with the Review Board and Ethics Committee of Pasteur Institute of Iran, the National Institute for Medical Research Development (Authorization code 943697), and Council Directive 2010/63EU of the European Parliament, and the Council of 22 September 2010 on the protection of animals used for scientific purposes.

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Radpour, M., Khoshkroodian, B., Asgari, T. et al. Interleukin 4 Reduces Brain Hyperexcitability after Traumatic Injury by Downregulating TNF-α, Upregulating IL-10/TGF-β, and Potential Directing Macrophage/Microglia to the M2 Anti-inflammatory Phenotype. Inflammation 46, 1810–1831 (2023). https://doi.org/10.1007/s10753-023-01843-0

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