Toll-like receptors TLR2, TLR4 and the DAMP HMGB-1 are involved in reactive gliosis and neuronal survival

ROSCISZEWSKI G, LUKIN J, CADENA MV, MURTA V, RAMOS AJ

Congreso; XXX Congreso de la Sociedad Argentina de Investigacion en Neurociencias (SAN),; 2015

Reactive gliosis is a generic glial response to brain injury that may have beneficial ordetrimental effects for neuronal survival. TLR are innate immunity receptors activated byHMGB1 and other DAMPs released by necrotic cells after brain injury and it is supposedthat they are involved in the reactive astrocytes conversion to the proinflammatoryneurodegenerativephenotype.In this work we studied the role of TLR2, TLR4 and HMGB-1 in the astroglial conversion tothe reactive phenotype and neuronal survival. First, we demonstrated that TLR2 and TLR4are expressed in the periphery of brain ischemic lesions induced by the corticaldevascularization model. Then, we showed that HMGB1 exposure (50-500 ng/ml) induceastrocytic stellation, NF-kB activation and, surprisingly, facilitated the expression ofantinflammatory genes in primary astrocytic culture. Conditioned media from HMGB1-exposed astrocytes (ACM-H) was used to treat primary cortical neuronal cultures. Neuronalviability was assayed by an enzymatic assay (MTT) and ACM-H showed to improve neuronalsurvival. ACM-H also showed a pro-synaptogenic effect when synaptic puncta werequantified by synapthophysin immunocytochemistry. On primary cultured microglia, ACMHinduced an M2-like profile identified by a panel of genes. Our results show that HMGB1induces reactive gliosis on astrocytes and, contrary to it was previously supposed, producesan anti-inflammatory and pro-survival effect.Grants: PICT2012-1424, CONICET, UBA