Investigação do papel do receptor metabotrópico de glutamato do tipo 5 (mGluR5) na resposta de astrócitos humanos a um estímulo inflamatório

Abstract

Neurological disorders are the second leading cause of death worldwide, with their origin and progression strongly linked to neuroinflammatory processes. The role of reactive astrocytes in neuroinflammation has gained increasing relevance, as these cells can influence the outcome of numerous pathologies in either a beneficial or detrimental manner. These astrocytes can release inflammatory mediators and affect synaptic connectivity, either by producing synaptogenic molecules or by eliminating synaptic terminals through phagocytosis. Thus, studying the pathways that regulate the activity of these cells is essential. The metabotropic glutamate receptor type 5 (mGluR5) can modulate the astrocytic response to the microenvironment, exerting opposite effects. Therefore, the aim of this study was to investigate the role of mGluR5 in the reactivity and functional alteration of human induced pluripotent stem cells (hiPSCs)-derived astrocytes in response to recombinant tumour necrosis factor alpha (rTNF-α). Inhibition of mGluR5 by 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced the secretion of pro-inflammatory cytokines (TNF-α and interleukin-6) after 4 hours of stimulation with rTNF-α, although this effect diminishes over time. CTEP also increased the phagocytosis of synaptoneurosomes by astrocytes, both in the absence and presence of rTNF-α, indicating that blocking mGluR5 is sufficient to promote the phagocytosis of synaptic material. Additionally, both inhibition of mGluR5 and stimulation with rTNF-α elevated the expression of the reactivity marker SERPINA3 and reduced the expression of synaptogenic molecules. These data suggest that mGluR5 plays a complex role in astrocytes, as its blockade can have potentially protective or harmful effects in inflammatory contexts.