Abstract
BackgroundAutophagy 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.MethodsHere, 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 (Aβ42) 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.ResultsAβ42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1β, TNF-α, and IL-6) or IL-1β 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-1β in the induction of autophagy in tri-cultures in the presence or absence of Aβ42. However, the vulnerability of the autophagic process in purified microglia to IL-1β was prevented by Aβ42.ConclusionThese findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1β 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.
Highlights
Autophagy is a major pathway of protein and organelle degradation in the lysosome
These findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1β in the induction of the microglial autophagy which could be the case in Alzheimer’s Disease (AD)
Tumor necrosis factor (TNF)-α treatment did not modify IL-6 levels, while IL-6 treatment induced a release of TNF-α but C16 had no effect [see Additional file 5]. This part of the results showed that: 1) a more moderate inflammation than previously induced by LPS led to an accumulation of acidic vesicles containing LC3 and p62 even in the presence of Amyloid peptide (Aβ42) in the tri-cultures; 2) this effect is ascribed only to IL-1β; 3) interestingly, the C16 compound prevented the production of intracellular factors TNF-α and IL-1β induced by exogenous IL-1β and the accumulation of p62 and LC3 in acidic vesicles; and 4) again, we found that increases in p62 and in the conversion of LC3-I in LC3-II were more pronounced in microglia, where Aβ42 reversed the IL-1β-induced increase in p62, underlying an increased sensitivity of microglial autophagy to inflammatory stress in an integrated cellular environment modeling the brain parenchyma
Summary
Autophagy is a major pathway of protein and organelle degradation in the lysosome. In addition to its role in cellular homeostasis, Dysfunctions of autophagy are widely implicated in pathological conditions, including cancer, metabolic and neurodegenerative disorders, and cardiovascular and pulmonary diseases [3]. Molecular mechanisms underlying these connections are not completely elucidated. Downregulation of both IFN responses to viral infection and proinflammatory cytokine responses to invading pathogens and the inhibition of inflammasomedependent maturation and secretion of proinflammatory cytokines (for example, IL-1β) have been demonstrated [4,5,6]. Following stimulation by lipopolysaccharide (LPS), autophagyrelated protein 16-1 (Atg16L1)-deficient macrophages produce high amounts of the proinflammatory cytokines IL-1β and IL-18, suggesting that autophagy might have an inhibitory effect on the maturation and secretion of proinflammatory cytokines [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
