cn6b00250_si_001.pdf (794.45 kB)
Dipeptidyl Vinyl Sulfone as a Novel Chemical Tool to Inhibit HMGB1/NLRP3-Inflammasome and Inflamma-miRs in Aβ-Mediated Microglial Inflammation
journal contribution
posted on 2016-10-31, 00:00 authored by Ana S. Falcão, Luís A. R. Carvalho, Gonçalo Lidónio, Ana R. Vaz, Susana D. Lucas, Rui Moreira, Dora BritesRapid
microglial activation and associated inflammatory pathways
contribute to immune-defense and tissue repair in the central nervous
system (CNS). However, persistent activation of these cells will ultimately
result in vast production of pro-inflammatory mediators and other
neurotoxic factors, which may induce neuronal damage and contribute
to chronic neurodegenerative diseases, as Alzheimer’s disease
(AD). Therefore, small molecules with immunomodulatory effects on
microglia may be considered as potential tools to counteract their
proinflammatory phenotype and neuroimmune dysregulation in such disorders.
Indeed, reducing amyloid-β (Aβ)-induced microglia activation
is believed to be effective in treating AD. In this study, we investigated
whether dipeptidyl vinyl sulfone (VS) was able to attenuate Aβ-mediated
inflammatory response using a mouse microglial (N9) cell line and
a solution containing a mixture of Aβ aggregates. We show that
low levels of VS are able to prevent cell death while reducing microglia
phagocytosis upon Aβ treatment. VS also suppressed Aβ-induced
expression of inflammatory mediators in microglia, such as matrix
metalloproteinase (MMP)-2 and MMP-9, as well as high-mobility group
box protein-1 (HMGB1), nod-like receptor protein 3 (NLRP3)-inflammasome,
and interleukin (IL)-1β. Interestingly, increased expression
of the two critical inflammation-related microRNAs (miR)-155 and miR-146a
in microglia upon Aβ treatment was also prevented by VS coincubation.
Taken together, VS emerges as a potential new therapeutic strategy
worthy of further investigation in improved cellular and animal models
of AD.