Effects of astrocyte‐targeted production of interleukin‐6 in the mouse on the host response to nerve injury

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine with a key role in the control of inflammatory/immune responses. In the central nervous system (CNS), an increase in IL-6 occurs in a wide range of pathological conditions such as excitotoxicity and traumatic brain injury. We evaluated the effects of astrocyte-targeted production of IL-6 in the CNS in the sterile-nerve injury model of facial nerve axotomy. To accomplish this, facial nerve transection was performed in transgenic mice (glial fibrillary acidic protein [GFAP]-IL6Tg) with IL-6 production under the GFAP promoter. Neuronal death, glial activation, lymphocyte recruitment, and integrin expression were evaluated by immunohistochemistry and flow cytometry from 3 to 28 days postinjury. Our findings revealed an increase in motor neuron cell death in GFAP-IL6Tg mice correlating with changes in the microglial activation pattern, characterized principally by less attachment to neurons and reduced expression of both CD11b and CD18. We also found a higher CD4(+) T-lymphocyte recruitment in GFAP-IL6Tg mice. In addition, changes in the expression pattern of different integrins and their receptors were observed in transgenic animals. Specifically, alterations in osteopontin expression in motor neurons and its receptors CD44 and CD49e in lymphocytes and microglia, respectively, which may account for the variations related to glial reactivity and lymphocyte infiltration. In conclusion, our results indicated that forced local production of IL-6 has a direct impact on the outcome of nerve injury in the CNS inducing an increase in neurodegeneration, changes in glial response, and lymphocyte recruitment as well as in the expression of different integrins and their receptors.

Astrocyte-targeted production of interleukin-6 reduces astroglial and microglial activation in the cuprizone demyelination model: Implications for myelin clearance and oligodendrocyte maturation

“…Our observations revealed that in comparison with control WT where Iba1 immunoreactivity in the mCC was very low (Fig. Qualitatively, we found that there is an increased number of Iba1 1 cells in the GFAP-IL6Tg compared with WT mice in agreement with other studies (Almolda et al, 2014). 6E,I).…”

“…The AI index was calculated by multiplying the percentage of the stained area by the MGVM, as already published (Almolda et al, 2014). Analysis was performed on 2-3 sections from each animal.…”

The expression of interleukin-6 and its receptor in various brain regions and their roles in exploratory behavior and stress responses

“…It has been demonstrated that the expression of IL-6 in astrocytes is significantly increased during inflammation, neurodegenerative disease and in other pathological conditions (Almolda et al, 2014;Chlodzinska et al, 2011;Erta et al, 2012;Jankord et al, 2010;Spooren et al, 2011). During infection and especially after LPS injections, IL-6 synthesis is induced in microglia.…”

Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10

“…By means of analySIS Ò software, both the percentage of area occupied by the immunolabelling as well as the intensity of the immunoreaction (Mean Grey Value Mean) was recorded for each photograph. For each marker, the AI index (Almolda et al, 2014) was calculated by multiplying the percentage of the immunolabelled area by the Mean Grey Value Mean.…”