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PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models.

The Journal of clinical investigation

Authors: Marta Baldrighi, Christian Doreth, Yang Li, Xiaohui Zhao, Emily F Warner, Hannah Chenoweth, Kamal Kishore, Yagnesh Umrania, David-Paul Minde, Sarah Winkler, Xian Yu, Yuning Lu, Alice Knapton, James Harrison, Murray Ch Clarke, Eicke Latz, Guillermo de Cárcer, Marcos Malumbres, Bernhard Ryffel, Clare E Bryant, Jinping Liu, Kathryn S Lilley, Ziad Mallat, Xuan Li

Unabated activation of NLRP3 inflammasome activation is linked with the pathogenesis of various inflammatory disorders. PLK1 has been widely studied for its role in mitosis. Here, employing both pharmacological and genetic approaches, we demonstrated that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased Bio-ID screen for PLK1 interactome in macrophages, we showed an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3, and identified the interacting domains. Mechanistically, we showed that PLK1 orchestrated microtubule organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL1B production in in-vivo inflammatory models, including lipopolysaccharide-induced endotoxemia and monosodium urate-induced peritonitis in mice. Our results uncover an unprecedented role of PLK1 in regulating NLRP3 inflammasome activation during interphase, and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.

PMID: 37698938

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