Lactoferrin potential to attenuate astroglial reactivity and stimulate the SOX-2 dependent reprogramming into neural precursor cells

Neurodegenerative diseases are characterized by chronic neuroinflammation and progressive loss of neu- rons. Upon inflammatory triggers, the astrocytes are activated assuming the neurotoxic A1 phenotype or neuroprotective A2 phenotype. Under pathological con- ditions, A1 astrocytes subset results to be predominant and neurotoxic effects prevails over supportive func- tions, playing a key role in the progression of neuro- degenerative disorders. However, a portion of reactive astrocytes can be dedifferentiated to acquire a neuronal phenotype in response to injury or chemical inducers. In the light of this evidence, the attenuation of glial reactivity, along with the astrocyte-to-neuron conver- sion, may be a promising strategy for the treatment of neurodegenerative disorders. The iron-binding protein lactoferrin can stimu- late neurogenesis, besides performing immunomodula- tory functions. This study aims to determine the effects of lactoferrin on astroglial reactivity and its potential to induce the astrocyte-to-neuron conversion. For this pur- pose, LPS-induced DI-TNC1 cell line was used as an in vitro model of prolonged inflammation. Astrocytes were pre-treated with lactoferrin (4μg/ml) for 24 hours fol- lowed by LPS (400 ng/ml) and examined after 2-, 9- and 16-days post-treatment. Results prove that lactofer- rin attenuates the glial reactivity by reducing the glial fibrillary acidic protein (GFAP) and Toll like receptor 4 (TLR4) expression, as well as improving the expression of the anti-inflammatory cytokine IL-10. Moreover, we found that lactoferrin promotes the astrocytes repro- gramming into neural precursor cells by inducing the expression of the reprogramming transcription factor SOX-2. Overall, this study demonstrates that lactofer- rin has the potential to attenuate neuroinflammation, in addition to inducing the astrocytes reprogramming into neural precursor cells, suggesting a potential innovative approach for the treatment of neurodegenerative diseases.