AMPK directly phosphorylates TBK1 to integrate glucose sensing into innate immunity.

Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation. AMPK, once activated, directly phosphorylates TBK1 at S511, which triggers IRF3 recruitment and the assembly of MAVS or STING signalosomes. Consistently, ablation or inhibition of AMPK, knockin of TBK1-S511A, or increased glucose levels compromised nucleic acid sensing, while boosting AMPK-TBK1 cascade by AICAR or TBK1-S511E knockin improves antiviral immunity substantially in various animal models. Thus, we identify TBK1 as an AMPK substrate, reveal the molecular mechanism coupling a dual sensing of glucose and nuclei acids, and report its physiological necessity in antiviral defense.

Low-dose metformin targets the lysosomal AMPK pathway through PEN2.

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1-4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.

Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.

Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity.

ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy.

Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.

Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

Liver-specific deficiency of unc-51 like kinase 1 and 2 protects mice from acetaminophen-induced liver injury.

unc-51-like autophagy activating kinase 1 and 2 (Ulk1/2) regulate autophagy initiation under various stress conditions. However, the physiological functions of these Ser/Thr kinases are not well characterized. Here, we show that mice with liver-specific double knockout (LDKO) of Ulk1 and Ulk2 (Ulk1/2 LDKO) are viable, but exhibit overt hepatomegaly phenotype. Surprisingly, Ulk1/2 LDKO mice display normal autophagic activity in hepatocytes upon overnight fasting, but are strongly resistant to acetaminophen (APAP)-induced liver injury. Further studies revealed that Ulk1/2 are also dispensable for APAP-induced autophagy process, but are essential for the maximum activation of c-Jun N-terminal kinase (JNK) signaling both in vivo and in isolated primary hepatocytes during APAP treatment. Mechanistically, APAP-induced inhibition of mechanistic target of rapamycin complex 1 releases Ulk1 from an inactive state. Activated Ulk1 then directly phosphorylates and increases the kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4/7), the upstream kinases and activator of JNK, and mediates APAP-induced liver injury. Ulk1-dependent phosphorylation of MKK7 was further confirmed by a context-dependent phosphorylation antibody. Moreover, activation of JNK and APAP-induced cell death was markedly attenuated in Mkk4/7 double knockdown hepatocytes reconstituted with an Ulk1-unphosphorylatable mutant of MKK7 compared to those in cells rescued with wild-type MKK7. CONCLUSION: Together, these findings reveal an important role of Ulk1/2 for APAP-induced JNK activation and liver injury, and understanding of this regulatory mechanism may offer us new strategies for prevention and treatment of human APAP hepatotoxicity. (Hepatology 2018;67:2397-2413).

ß-Catenin 1 and ß-catenin 2 play similar and distinct roles in left-right asymmetric development of zebrafish embryos.

ß-Catenin-mediated canonical Wnt signaling has been found to be required for left-right (LR) asymmetric development. However, the implication of endogenous ß-catenin in LR development has not been demonstrated by loss-of-function studies. In zebrafish embryos, two ß-catenin genes, ß-catenin 1 (ctnnb1) and ß-catenin 2 (ctnnb2) are maternally expressed and their zygotic expression occurs in almost all types of tissues, including Kupffer's vesicle (KV), an essential organ that initiates LR development in teleost fish. We demonstrate here that morpholino-mediated knockdown of ctnnb1, ctnnb2, or both, in the whole embryo or specifically in dorsal forerunner cells (DFCs) interrupts normal asymmetry of the heart, liver and pancreas. Global knockdown of ctnnb2 destroys the midline physical and molecular barrier, while global knockdown of ctnnb1 impairs the formation of the midline molecular barrier. Depletion of either gene or both in DFCs/KV leads to poor KV cell proliferation, abnormal cilia formation and disordered KV fluid flow with downregulation of ntl and tbx16 expression. ctnnb1 and ctnnb2 in DFCs/KV differentially regulate the expression of charon, a Nodal antagonist, and spaw, a key Nodal gene for laterality development in zebrafish. Loss of ctnnb1 in DFCs/KV inhibits the expression of charon around KV and of spaw in the posterior lateral plate mesoderm, while ctnnb2 knockdown results in loss of spaw expression in the anterior lateral plate mesoderm with little alteration of charon expression. Taken together, our findings suggest that ctnnb1 and ctnnb2 regulate multiple processes of laterality development in zebrafish embryos through similar and distinct mechanisms.

Mechanism and physiological significance of growth factor-related autophagy.

Growth factors, typically defined as natural substances capable of stimulating cell growth and differentiation, are vital regulators for the survival of metazoan cells. In this review, we will focus on growth factor signaling pathways that are closely related to autophagy induction and discuss the critical roles of this fascinating cellular process in intracellular energy homeostasis, cell fate determination, and pathophysiological regulation.

The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK.

Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.

AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.

The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

Cidea-deficient mice have lean phenotype and are resistant to obesity.

The thermogenic activity of brown adipose tissue (BAT), important for adaptive thermogenesis and energy expenditure, is mediated by the mitochondrial uncoupling protein1 (Ucp1) that uncouples ATP generation and dissipates the energy as heat. We show here that Cidea, a protein of unknown function sharing sequence similarity with the N-terminal region of DNA fragmentation factors Dffb and Dffa, is expressed at high levels in BAT. Cidea-null mice had higher metabolic rate, lipolysis in BAT and core body temperature when subjected to cold treatment. Notably, Cidea-null mice are lean and resistant to diet-induced obesity and diabetes. Furthermore, we provide evidence that the role of Cidea in regulating thermogenesis, lipolysis and obesity may be mediated in part through its direct suppression of Ucp1 activity. Our data thus indicate a role for Cidea in regulating energy balance and adiposity.

The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling.

AIMS: Wnt signalling is involved in cellular homeostasis and development. Dysregulation of the Wnt signalling pathway has been linked to colorectal cancer. The orphan nuclear receptor TR3 plays important roles in proliferation and apoptosis. In this study, we investigated how TR3 suppresses intestinal tumorigenesis by regulating Wnt signalling. METHODS: Intestinal polyps were quantified in Apc(min/+), Apc(min/+)/TR3(-/-) and Apc(min/+)/villin-TR3 mice. Wnt signalling activity was evaluated by assessing ß-galactosidase activity in a BAT-Gal reporter strain. The TR3 agonist cytosporone B was used to evaluate the role of TR3 in intestinal tumorigenesis. Crosstalk between TR3 and ß-catenin/TCF4 was analysed by molecular methods in colorectal cancer cells. The phosphorylation of TR3 by glycogen synthase kinase (GSK) 3ß and the correlation between GSK3ß activity and TR3 phosphorylation were evaluated in clinical samples and colorectal cancer cells. RESULTS: TR3 was found to significantly suppress Wnt signalling activity and the proliferation of intestinal epithelial cells. Apc(min/+)/TR3(-/-) mice developed more intestinal polyps than Apc(min/+)/TR3(+/+) mice, whereas either transgenic overexpression of TR3 in the intestine or treatment with cytosporone B in Apc(min/+) mice significantly decreased intestinal tumour number. Mechanistically, TR3 disrupted the association of ß-catenin and TCF4 on chromatin and facilitated the recruitment of transcriptional co-repressors to the promoters of Wnt signalling target genes. However, TR3 was phosphorylated by GSK3ß in most clinical colorectal cancers, which attenuated the inhibitory activity of TR3 towards Wnt signalling. CONCLUSIONS: TR3 is a negative regulator of Wnt signalling and thus significantly suppresses intestinal tumorigenesis in Apc(min/+) mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3ß in clinical colorectal cancers.

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate.

Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.

Cdk5-mediated phosphorylation of Axin directs axon formation during cerebral cortex development.

Axon formation is critical for the establishment of connections between neurons, which is a prerequisite for the development of neural circuitry. Kinases such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase-3ß (GSK-3ß), have been implicated to regulate axon outgrowth. Nonetheless, the in vivo roles of these kinases in axon development and the underlying signaling mechanisms remain essentially unknown. We report here that Cdk5 is important for axon formation in mouse cerebral cortex through regulating the functions of axis inhibitor (Axin), a scaffold protein of the canonical Wnt pathway. Knockdown of Axin in utero abolishes the formation and projection of axons. Importantly, Axin is phosphorylated by Cdk5, and this phosphorylation facilitates the interaction of Axin with GSK-3ß, resulting in inhibition of GSK-3ß activity and dephosphorylation of its substrate collapsin response mediator protein-2 (CRMP-2), a microtubule-associated protein. Specifically, both phosphorylation of Axin and its interaction with GSK-3ß are critically required for axon formation in mouse cortex development. Together, our findings reveal a new regulatory mechanism of axon formation through Cdk5-dependent phosphorylation of Axin.

Molecular basis of Wnt activation via the DIX domain protein Ccd1.

The Wnt signaling plays pivotal roles in embryogenesis and cancer, and the three DIX domain-containing proteins, Dvl, Axin, and Ccd1, play distinct roles in the initiation and regulation of canonical Wnt signaling. Overexpressed Dvl has a tendency to form large polymers in a cytoplasmic punctate pattern, whereas the biologically active Dvl in fact forms low molecular weight oligomers. The molecular basis for how the polymeric sizes of Dvl proteins are controlled upon Wnt signaling remains unclear. Here we show that Ccd1 up-regulates canonical Wnt signaling via acting synergistically with Dvl. We determined the crystal structures of wild type Ccd1-DIX and mutant Dvl1-DIX(Y17D), which pack into "head-to-tail" helical filaments. Structural analyses reveal two sites crucial for intra-filament homo- and hetero-interaction and a third site for inter-filament homo-assembly. Systematic mutagenesis studies identified critical residues from all three sites required for Dvl homo-oligomerization, puncta formation, and stimulation of Wnt signaling. Remarkably, Ccd1 forms a hetero-complex with Dvl through the "head" of Dvl-DIX and the "tail" of Ccd1-DIX, depolymerizes Dvl homo-assembly, and thereby controls the size of Dvl polymer. These data together suggest a molecular mechanism for Ccd1-mediated Wnt activation in that Ccd1 converts latent polymeric Dvl to a biologically active oligomer(s).

A beta-catenin-independent dorsalization pathway activated by Axin/JNK signaling and antagonized by aida.

Axin is a scaffold protein that controls multiple important pathways, including the canonical Wnt pathway and JNK signaling. Here we have identified an Axin-interacting protein, Aida, which blocks Axin-mediated JNK activation by disrupting Axin homodimerization. During investigation of in vivo functions of Axin/JNK signaling and aida in development, it was found that Axin, besides ventralizing activity by facilitating beta-catenin degradation, possesses a dorsalizing activity that is mediated by Axin-induced JNK activation. This dorsalizing activity is repressed when aida is overexpressed in zebrafish embryos. Whereas Aida-MO injection leads to dorsalized embryos, JNK-MO and MKK4-MO can ventralize embryos. The anti-dorsalization activity of aida is conferred by its ability to block Axin-mediated JNK activity. We further demonstrate that dorsoventral patterning regulated by Axin/JNK signaling is independent of maternal or zygotic Wnt signaling. We have thus identified a dorsalization pathway that is exerted by Axin/JNK signaling and its inhibitor Aida during vertebrate embryogenesis.

Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.

Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.

Identification of serum metabolites enhancing inflammatory responses in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.