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Cyclin J-CDK complexes limit innate immune responses by reducing proinflammatory changes in macrophage metabolism

Chong, Yee Kien 京都大学 DOI:10.14989/doctor.k24140

2022.07.25

概要

The activation of macrophages is controlled by the dynamic metabolic changes induced by extracellular stimuli such as Toll-like receptor (TLR) ligands and viral infection, as well as environmental changes like hypoxia. Particularly, glycolysis activation as well as mitochondrial reactive oxygen species (ROS) production are known to promote inflammatory responses in macrophages. Despite elaborate studies on innate immune metabolism, the regulatory mechanism of macrophage metabolic changes is not fully understood.

The aim of this study was to investigate the function of Cyclins in macrophage innate immune responses. Using publicly available database of macrophage activation, an atypical cyclin, called cyclin J, was identified to exhibit unusual inducibility by TLR ligands such as LPS and Type I Interferon. Cyclin J was then demonstrated to function as an unconventional repressor of TLR-induced inflammatory responses in macrophages using both overexpression and genetic depletion approaches. In-depth analyses revealed that Cyclin J affects metabolic activity of macrophage through suppression of glycolysis processes, shown by the depletion in gene expression encoded for glycolytic genes, production of HIF-1α, and reduction in glycolysis process. Cyclin J was further identified to affect mitochondrial oxidative phosphorylation with notable changes in mitochondrial fitness, including reduced membrane potential and capability of ROS production upon activation. Mechanistically, Cyclin J associates with Cyclin-dependent kinases (CDKs) and the interaction is required for its immune-regulatory function in macrophages. As the Cyclin/CDK complex triggers phosphorylation on a set of specific substrates, phosphoproteomic analysis was then performed and a unique set of proteins phosphorylated by the Cyclin J/CDK complex was discovered in macrophages. Further analyses uncovered that Cyclin J targets immuno-metabolic signaling in macrophages through FoxK1 and Drp1, respectively.

Cyclin J/CDK-mediated phosphorylation of FoxK1 resulted in impaired glycolytic gene transcription by the impairment of its nuclear localization. On the other hand, Drp1 phosphorylation by Cyclin J/CDK led to mitochondrial fission and suppression of ROS production. Overall, Cyclin J coordinately controls metabolism and thereby suppresses inflammatory responses in macrophages. To address the functional roles of Cyclin J in macrophages in vivo, sub-lethal dose of LPS was injected into mice to mimic septic shock. The results showed that myeloid-specific Cyclin J-deficient mice experienced higher fatality with heightened serum pro-inflammatory cytokine profile compared with control mice.

On the other hand, mice were systemically infected with S. aureus infection and showed that myeloid-specific Cyclin J-deficient mice were protected from succumb to fatality with lower bacterial burden in multiple organs together with elevated cytokine production. Beyond acute infection model, the role of Cyclin J was examined using cancer model using both xenograft and colitis-associated cancer models, in which Cyclin J could mediate tumor progression through affecting the behavior of tumor associated macrophages, with elevation of pro-tumoral and pro-inflammatory characters with the change in metabolic status such as glycolysis. In summary, this study provides a new perspective of Cyclin J-CDK-mediated immuno-regulation by identifying a novel role of Cyclin J in controlling macrophage function via immuno-metabolism. Our evidence showed that global inhibition or activation of CDKs can affect cellular functions such as cell cycling and transcription broadly, in addition to the immune regulation. Therefore, this new finding provides a different perspective for the establishment of novel therapeutic approaches, in which developing small molecules targeting Cyclin expression in modulating CDK activity of macrophage are promising in controlling both infectious diseases and tumor progression in future.

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