Chronic IL-6 overproduction induces a tolerogenic response in aged mice after peripheral nerve injury

Highlights/Main pointsO_LIAstrocyte-targeted IL-6 overproduction during aging increases basal microglial acivation in the facial nucleus. C_LIO_LIDuring aging, chronic IL-6 overproduction does not modify microglial response after peripheral nerve injury but increases T-lymphocyte infiltration. C_LIO_LIChronic IL-6 overproduction in aged mice does not modify facial motor neuron survival after facial nerve axotomy. C_LI Interleukin-6 (IL-6) is the main cytokine controlling neuroinflammation and microglial activation during aging, and the increase of IL-6 levels correlate well with chronic neuroinflammation and age-related neurodegenerative diseases. Despite the relevance of IL-6 in these conditions, the effect of this cytokine in microglia activation and neuroinflammation upon CNS injuries during aging has been scarcely explored. Previous results from our group showed that adult and aged transgenic mice with astrocyte-targeted overproduction of IL-6 (GFAP-IL6Tg) presented features of a primed microglial phenotype in basal conditions compared to wild-type (WT) mice, and that after CNS lesions, microglia showed and exacerbated response associated with increased neuronal death in adult mice. In this work, we aimed to study whether chronic IL-6 overproduction influenced microglia response to CNS injury during aging. With this aim, we performed facial nerve axotomy (FNA) in aged 21-23-month-old WT and GFAP-IL6Tg animals, and analysed facial motor neuron (FMN) survival, glial reactivity, antigen presentation, and lymphocyte infiltration both at basal conditions (non-lesioned) and after FNA. Our results showed that non-lesioned aged transgenic mice presented higher Iba1, CD11b, and CD68 levels than aged WT mice, indicative of a priming effect in the aged facial nucleus. After FNA, we detected similar levels of microglial and astroglia activation, but a remarkable increase in T-lymphocyte infiltration in GFAP-IL6Tg axotomized group. Despite slight differences in the neuroinflammatory response, aged GFAP-IL6Tg animals showed a similar rate of FMN death compared to aged WT mice. Overall, our work shows that transgenic IL-6 overproduction induces a primed microglial phenotype under basal conditions in aged animals, with a reduced fold-increase in the microglial response after FNA compared to aged WT mice and similar lesion outcomes, suggestive of a tolerant microglial phenotype. This study suggests a tolerant effect of chronic IL-6 overproduction in microglia during aging in basal conditions and after CNS lesions.