TY  - JOUR
AU  - Braatz, Charlotte
AU  - Komes, Max
AU  - Ravichandran, Kishore
AU  - Garcia de Fragas, Matheus
AU  - Griep, Angelika
AU  - Schwartz, Stephanie
AU  - McManus, Roisin
AU  - Heneka, Michael T
TI  - NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro.
JO  - Journal of neurochemistry
VL  - 168
IS  - 10
SN  - 0022-3042
CY  - Oxford
PB  - Wiley-Blackwell
M1  - DZNE-2023-00413
SP  - 3467 - 3481
PY  - 2024
AB  - Alzheimer's disease (AD) is associated with the cerebral deposition of Amyloid-β (Aβ) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin-1β (IL-1β) and interleukin-18 (IL-18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here, we test whether NLRP3-directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP-1 cells. NLRP3 mRNA degradation was achieved at 72 h of ASO treatment in primary murine microglia. Consequently, NLRP3-directed ASOs significantly reduced the levels of cleaved caspase-1 and mature IL-1β when microglia were either activated by LPS and nigericin or LPS and Aβ. In human THP-1 cells NLRP3-targeted ASOs also significantly reduced the LPS plus nigericin- or LPS plus Aβ-induced release of mature IL-1β. Together, NLRP3-directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL-1β in primary murine microglia and THP-1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically.
KW  - Microglia: metabolism
KW  - Microglia: drug effects
KW  - Animals
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - Humans
KW  - Mice
KW  - Oligonucleotides, Antisense: pharmacology
KW  - Mice, Inbred C57BL
KW  - Amyloid beta-Peptides: metabolism
KW  - Interleukin-1beta: metabolism
KW  - Inflammasomes: metabolism
KW  - THP-1 Cells
KW  - Cells, Cultured
KW  - Alzheimer's disease (Other)
KW  - Aβ (Other)
KW  - NLRP3 inflammasome (Other)
KW  - antisense oligonucleotides (Other)
KW  - innate immunity (Other)
KW  - microglia (Other)
KW  - neuroinflammation (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36799439
DO  - DOI:10.1111/jnc.15778
UR  - https://pub.dzne.de/record/257344
ER  -