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.

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 driveof 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.