Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a major health problem with high rates of mortality and morbidity worldwide. The response of the brain to TBI is orchestrated by a number of cytokines, including interleukin‐6 (IL‐6). IL‐6 is a major cytokine in the central nervous system and it is produced by different cells, such as neurons, glial cells, and endothelial cells. Since glial cells are one of the most important sources and targets of IL‐6, we have examined the role of microglia‐derived IL‐6 in normal conditions and following a model of TBI, cryolesion of the somatosensorial cortex. To this end, tamoxifen‐inducible microglial IL‐6‐deficient (Il6ΔMic, using Cx3cr1 CreER model) mice and control (Il6lox/lox) mice were used. In normal conditions, microglial IL‐6 deficiency reduced deambulation and exploratory behavior and decreased anxiety in a sex‐dependent manner. The transcriptome profile following cryolesion was dramatically altered 1 day post‐lesion in Il6ΔMic compared with Il6lox/lox mice. However, the phenotype of Il6ΔMic mice was less compromised in the following days, suggesting that compensatory mechanisms are at play.

Interleukin-6 Derived from the Central Nervous System May Influence the Pathogenesis of Experimental Autoimmune Encephalomyelitis in a Cell-Dependent Manner

“…It is feasible that the roles of these cellular sources of IL-6 in the control of body weight can be related to these results to some extent. Indeed, we did observe a major phenotype of IL6:SYN1 KO female mice, in line with the present results, when fed with a high-fat diet [40,48]. Taking all these data together, our results reinforce the idea that IL-6 derived from different brain cellular sources may participate in EAE pathogenesis in a cell-type specific manner.…”

“…Therefore, in all mice we assessed specific and nonspecific Il6 recombination in DNA isolated from brain and tail and liver samples, respectively. In accordance to previous results using GFAP-Cre, Syn1-Cre, and Cx3cr1 CreER mice [40,48], ectopic Il6 recombination (presumably indicating germline recombination) was very high in the former two (~60-90%, respectively) and nearly absent in the latter. Therefore, we only used mice that showed no peripheral recombination, which severely restricted the number of groups possible.…”

“…The production of cytokines and IL-6, in particular, is increased in the spinal cord during EAE [32,51], agreeing with our results in measuring Il6 mRNA levels. By using IL6:GFAP KO, IL6:SYN1 KO, and IL6:CX3CR1 KO mice, significant decreases of Il6 mRNA levels could be expected compared to their respective WT animals since astrocytes, neurons, and microglia, respectively, are potential sources of this cytokine; we recently described the effectiveness of these three Cre mouse models [40,48]. Il6 mRNA levels during EAE were indeed decreased in IL6:GFAP KO and IL6:CX3CR1 KO mice, which is not surprising since astrocytes and microglia are two of the main brain cellular sources of IL-6 [3,52].…”

A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner: microglial IL-6 regulation of experimental autoimmune encephalomyelitis

“…Their littermates were also administered with TAM to control the effects of TAM in the analyzed parameters. TAM (Sigma 5648) was dissolved in ethanol at a concentration of 10 mg/100 μl by shaking and heating at 37°C [26]; next, the solution was diluted with sunflower oil to 10 mg/ml and one daily dose of 100 μl (1 mg) was injected intraperitoneally to each mouse.…”

“…After dissociation, debris and erythrocytes were removed and microglia were isolated using magnetic microbeads against Cluster of differentiation molecule 11b (CD11b; Miltenyi 130-093-634) following the manufacturer's instructions. The purity of microglia in CD11b+ cell population was previously checked in [26]. The CD11b-negative flow-through was named "remaining sample".…”