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Intracellular NAD⁺ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.

ABSTRACT: Nicotinamide adenine dinucleotide (NAD⁺) is an important cofactor in many redox and non-redox NAD⁺-consuming enzyme reactions. Intracellular NAD⁺ level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD⁺ depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages. NAD⁺-depleted mouse bone marrow-derived macrophages (BMDMs) exhibited similar levels of proinflammatory cytokine production in response to LPS or poly (I:C) stimulation compared with untreated cells. Instead, FK866 facilitated robust caspase-1 activation in BMDMs in the presence of NLRP3-activating signals such as ATP and nigericin, a potassium ionophore. However, this FK866-mediated caspase-1 activation was completely abolished in Nlrp3-deficient macrophages. FK866 plus nigericin stimulation caused an NLRP3-dependent assembly of inflammasome complex. In contrast, restoration of NAD⁺ level by supplementation with nicotinamide mononucleotide abrogated the FK866-mediated caspase-1 cleavage. FK866 did not induce or increase the expression levels of NLRP3 and interleukin (IL)-1β but drove mitochondrial retrograde transport into the perinuclear region. FK866-nigericin-induced mitochondrial transport is critical for caspase-1 cleavage in macrophages. Consistent with the in vitro experiments, intradermal coinjection of FK866 and ATP resulted in robust IL-1β expression and caspase-1 activation in the skin of wild-type, but not Nlrp3-deficient mice. Collectively, our data suggest that NAD⁺ depletion provides a non-transcriptional priming signal for NLRP3 activation via mitochondrial perinuclear clustering, and aging-associated NAD⁺ decline can trigger NLRP3 inflammasome activation in ATP-rich environments.

SUBMITTER: Shim DW

PROVIDER: S-EPMC8722528 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Paclitaxel is a chemotherapeutic drug commonly used to treat different types of cancer. In addition to its antitumor effect, paclitaxel is also known to promote Toll-like receptor (TLR) 4-dependent inflammatory responses, which may lower its chemotherapeutic efficacy. However, it remains unclear whether paclitaxel is able to affect inflammasome signaling in myeloid or cancer cells. Therefore, we examined the potential effect of paclitaxel on the activation of an inflammasome complex by examining caspase-1 activation and interleukin (IL)-1β secretion in bone marrow-derived macrophages (BMDMs). The results showed that treatment with paclitaxel alone or following LPS priming failed to trigger the secretion of active caspase-1 and IL-1β from BMDMs. However, paclitaxel could induce robust activation of caspase-1 in BMDMs in the presence of NLRP3 inflammasome-activating signal 2, such as ATP or nigericin. This paclitaxel/ATP-mediated inflammasome activation was completely abrogated in Nlrp3-deficient macrophages. Mechanistically, paclitaxel treatment induced robust activation of the TLR4 signaling cascade, including phosphorylation of IκB and JNK and upregulation of proinflammatory cytokine mRNA levels in a TLR4-dependent manner. In contrast, paclitaxel treatment alone did not induce mitochondrial damages such as the loss of the mitochondrial membrane potential and production of mitochondrial ROS. These findings suggest that paclitaxel can drive the priming of signal-mediated events for NLRP3 activation but not a second signal-triggered phenomenon such as mitochondrial damage. This suggestion was supported by the observations that paclitaxel treatment 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 that paclitaxel is able to facilitate the activation of NLRP3 inflammasome signaling in a certain physiological environment.

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Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.

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Intracellular NAD⁺ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.