Bystander activation of microglia by Brucella abortus-infected astrocytes induces neuronal death via IL-6 trans-signaling

JULIA RODRÍGUEZ; JULIA DE SANTIS ARÉVALO; VIDA A. DENNIS; ANA M. RODRÍGUEZ; GUILLERMO H. GIAMBARTOLOMEI

FRontiers in immunology

Frontiers media SA

Año: 2024 vol. 14

1664-3224

Inflammation plays a key role in the pathogenesis of neurobrucellosis where glialcell interactions are at the root of this pathological condition. In this study, wepresent evidence indicating that soluble factors secreted by Brucella abortusinfectedastrocytes activate microglia to induce neuronal death. Culturesupernatants (SN) from B. abortus-infected astrocytes induce the release ofpro-inflammatory mediators and the increase of the microglial phagocyticcapacity, which are two key features in the execution of live neurons byprimary phagocytosis, a recently described mechanism whereby B. abortusactivatedmicroglia kills neurons by phagocytosing them. IL-6 neutralizationcompletely abrogates neuronal loss. IL-6 is solely involved in increasing thephagocytic capacity of activated microglia as induced by SN from B. abortusinfectedastrocytes and does not participate in their inflammatory activation.Both autocrine microglia-derived and paracrine astrocyte-secreted IL-6 endowmicroglial cells with up-regulated phagocytic capacity that allows them tophagocytose neurons. Blocking of IL-6 signaling by soluble gp130 abrogatesmicroglial phagocytosis and concomitant neuronal death, indicating that IL-6activates microglia via trans-signaling. Altogether, these results demonstrate thatsoluble factors secreted by B. abortus-infected astrocytes activate microglia toinduce, via IL-6 trans-signaling, the death of neurons. IL-6 signaling inhibitionmay thus be considered a strategy to control inflammation and CNS damagein neurobrucellosis.