The platelet NLRP3 inflammasome is upregulated in a murine model of pancreatic cancer and promotes platelet aggregation and tumor growth

Abstract

Platelets are activated in solid cancers, including pancreatic ductal adenocarcinoma (PDA), a highly aggressive malignancy with a devastating prognosis and limited therapeutic options. The mechanisms by which activated platelets regulate tumor progression are poorly understood. The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a key inflammatory mechanism recently identified in platelets, which controls platelet activation and aggregation. In an orthotopic PDA mouse model involving surgical implantation of Panc02 murine cancer cells into the tail of the pancreas, we show that the NLRP3 inflammasome in circulating platelets is upregulated in pancreatic cancer. Pharmacological inhibition or genetic ablation of NLRP3 in platelets resulted in decreased platelet activation, platelet aggregation, and tumor progression. Moreover, interfering with platelet NLRP3 signaling significantly improved survival Sebastian Vogel,

Innate immune receptors in platelets and platelet-leukocyte interactions

“…During dengue infection, platelet inflammasome activation requires reactive oxygen species generated in mitochondria, but not ATP release from granules 50,83 (see Section 6.1). Hence, other evidence regarding NLRP3 and IL‐1β participation in platelet prothrombotic responses have emerged 15,86–90 …”

“…In a murine model of pancreatic cancer, platelet NLRP3 signaling is up‐regulated promoting platelet activation and aggregation 89 . Transfusion of NLRP3‐deficient platelets after platelet depletion improved the survival of wild‐type mice to pancreatic cancer compared to animals receiving wild‐type platelets 89 . Nevertheless, the triggers of NLRP3‐induced platelet responses in this model remain unknown.…”

“…Hence, other evidence regarding NLRP3 and IL-1 participation in platelet prothrombotic responses have emerged. 15,[86][87][88][89][90] NOD2 receptor is characterized by 2 caspase activation and recruitment N-terminal domains and recognizes muramyl dipeptide (MDP) from Gram-positive and Gram-negative bacteria. 91,92 Platelet NOD2 activation with MDP potentiates platelet aggrega-tion, ATP release, and clot retraction in response to prothrombotic stimuli.…”

Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients

“…NLRP3 inhibition impairs the retraction of clots in human platelets [ 34 ]. In a murine model of pancreatic cancer, the platelet NLRP3 inflammasome is upregulated and promotes platelet aggregation and tumor formation [ 35 ]. Platelet activation triggers the release of intragranular contents like ATP.…”

“…The key role of platelets in blood clot formation is primary hemostasis, which involves adherence to damaged surfaces, binding to procoagulants, and forming aggregates to avoid blood loss. NLRP3 in platelets is upregulated with increased caspase-1 activity in pancreatic cancer, as demonstrated in a mouse model [ 35 ]. The decrease in platelet activation and aggregation can be induced via the downregulation of NLRP3 [ 35 ].…”