Involvement of interleukin-1? in the autophagic process of microglia: relevance to Alzheimer's disease.

ABSTRACT:

Background

Autophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer's Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined.

Methods

Here, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (A?42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls' test.

Results

A?42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1?, TNF-?, and IL-6) or IL-1? alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1? in the induction of autophagy in tri-cultures in the presence or absence of A?42. However, the vulnerability of the autophagic process in purified microglia to IL-1? was prevented by A?42.

Conclusion

These findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1? in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.

SUBMITTER: Francois A 

PROVIDER: S-EPMC3878742 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature