Detrimental effects of HMGB-1 require microglial-astroglial interaction: Role in the status epilepticus-induced neuroinflammation.

CADENA, VANESA; LUKIN, JERÓNIMO; VILLARREAL, ALEJANDRO; RAMOS, ALBERTO JAVIER; ROSCISZEWSKI, GERARDO; CIERI, MARÍA BELÉN; MURTA, VERONICA; GOMES, FLÁVIA C. A.; AUZMENDI, JERÓNIMO; ROSSI, ALICIA R.; REINÉS, ANALIA

Frontiers in Cellular Neuroscience

Frontiers

Lugar: Lausanne; Año: 2019 vol. 13

1662-5102

Temporal Lobe Epilepsy (TLE) is the most common form of human epilepsy and available treatments with antiepileptic drugs arenot disease-modifying therapies. The neuroinflammation, neuronal death and exacerbated plasticity that occur during the silentperiod, following the initial precipitating event (IPE), seem to be crucial for epileptogenesis. Damage Associated Molecular Patterns(DAMP) such as HMGB-1, are released early during this period concomitantly with a phenomenon of reactive gliosis andneurodegeneration. Here, using a combination of primary neuronal and glial cell cultures, we show that exposure to HMGB-1induces dendrite loss and neurodegeneration in a glial-dependent manner. In glial cells, loss of function studies showed that HMGB-1exposure induces NF-kB activation by engaging a signaling pathway that involves TLR2, TLR4 and RAGE. In the absence of glial cells,HMGB-1 failed to induce neurodegeneration of primary cultured cortical neurons. Moreover, purified astrocytes were unable tofully respond to HMGB-1 with NF-kB activation and required microglial cooperation. In agreement, in vivo HMGB-1 blockage withglycyrrhizin, immediately after pilocarpine-induced status epilepticus, reduced neuronal degeneration, reactive astrogliosis andmicrogliosis in the long term. We conclude that microglial-astroglial cooperation is required for astrocytes to respond to HMGB-1and to induce neurodegeneration. Disruption of this HMGB-1 mediated signaling pathway shows beneficial effects by reducingneuroinflammation and neurodegeneration after status epilepticus. Thus, early treatment strategies during the latency periodaimed at blocking downstream signaling pathways activated by HMGB-1 are likely to have a significant effect in theneuroinflammation and neurodegeneration that are proposed as key factors in epileptogenesis.