Damage associated molecular pattern HMGB-1 effects in neuronal survival and propagation of reactive gliosis

ROSCISZEWSKI G, LUKIN J, CADENA V, GOMES F, RAMOS AJ

Buenos Aires

Congreso; Federation of Neurosciences Societies (FALAN); 2016

Federation of Neuroscience Societes of Latin America and Caribe

Damage associated molecular pattern molecules such as HMGB-1 are intracellular components that are able to activate innate immune system when released to extracellular space. Innate immunity effectors in the CNS are astrocytes and microglia and reactive gliosis is the morphological consequence of such activation. There is an oversimplification in considering reactive gliosis as an on/off mechanism with neurodegenerative consequences in the brain. Having in mind that brain ischemia induce a dramatic HMGB-1 release from necrotic neurons, we dissected here the HMGB-1 effects on astrocytes, microglia and primary neurons. Our results showed that purified primary cortical neurons exposed to HMGB-1 presented an increase in the number of synaptic puncta immunolabelled with synaptophisin/debrin per neuron without significative increase in the LDH release or evidences of nuclear alterations with DAPI. On the other hand, HMGB-1 direct application on astrocytes induced NF-kB activation but lesser expression of proinflammatory genes such as iNOS compared with 25 ng/ml LPS exposure. Similarly, on microglia we observed that HMGB-1 induced M2 profile genes and TREM-2 expression. Furthermore, conditioned medium from HMGB-1 exposed astrocytes also showed synaptogenic and pro-survival effects on neurons and was anti-inflammatory in microglia. Finally, HMGB-1 effects were dependent of TLR2 but not TLR4 expression as showed in glial cultures from TLR-2 or -4 knock out mice and NF-kB dependent as they were blocked with BAY117082. We conclude that DAMP HMGB-1 induces innate immunity activation and reactive gliosis but without showing astroglial polarization to the proinflammatory-neurodegenerative profile and probably facilitating neuronal survival. Grants: PICT 2012-1424, PIP CONICET