Chemotherapeutic Agent Paclitaxel Mediates Priming of NLRP3 Inflammasome Activation

Abstract

Paclitaxelis achemotherapeuticdrug commonly used to treat different types of cancer. In addition to its antitumor effect,paclitaxelis also known to promote Toll-like receptor (TLR) 4-dependent inflammatory responses, which may lower itschemotherapeuticefficacy. However, it remains unclear whetherpaclitaxelis able to affectinflammasomesignaling in myeloid or cancer cells. Therefore, we examined the potential effect ofpaclitaxelon theactivationof aninflammasomecomplex by examining caspase-1activationand interleukin (IL)-1β secretion in bone marrow-derived macrophages (BMDMs). The results showed that treatment withpaclitaxelalone or following LPSprimingfailed to trigger the secretion ofactivecaspase-1 and IL-1β from BMDMs. However,paclitaxelcould induce robustactivationof caspase-1 in BMDMs in the presence ofNLRP3inflammasome-activatingsignal 2, such as ATP or nigericin. Thispaclitaxel/ATP-mediatedinflammasomeactivationwas completely abrogated inNlrp3-deficient macrophages. Mechanistically,paclitaxeltreatment induced robustactivationof the TLR4 signaling cascade, including phosphorylation of IκB and JNK and upregulation of proinflammatory cytokine mRNA levels in a TLR4-dependent manner. In contrast,paclitaxeltreatment alone did not induce mitochondrial damages such as the loss of the mitochondrial membrane potential and production of mitochondrial ROS. These findings suggest thatpaclitaxelcan drive theprimingof signal-mediatedevents forNLRP3activationbut not a second signal-triggered phenomenon such as mitochondrial damage. This suggestion was supported by the observations thatpaclitaxeltreatment caused robust IL-1β production in macrophages in the presence of cell-free medium derived from growth of injured cells and also in the spleen of mice. Collectively, our data strongly indicate thatpaclitaxelis able to facilitate theactivationofNLRP3inflammasomesignaling in a certain physiological environment.