Inducible Nitric Oxide Synthase Downmodulates Contact Hypersensitivity by Suppressing Dendritic Cell Migration and Survival

Sugita, Kazunari; Kabashima, Kenji; Yoshiki, Ryutaro; Ikenouchi-Sugita, Atsuko; Tsutsui, Masato; Nakamura, Jun; Yanagihara, Nobuyuki; Tokura, Y.

doi:10.1038/jid.2009.288

Cited by 14 publications

(10 citation statements)

References 32 publications

(27 reference statements)

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“…Additionally, NO has been reported to affect a wide range of DC-mediated inflammatory functions from cellular activation to T cell stimulation (27–31). We have shown that NO production by inflammatory DCs results in auto-crine disruption of mitochondrial respiration (6), presumably through the inhibition of key iron-containing enzymes of the electron transport chain (32–34).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Target of Rapamycin Inhibition Extends Cellular Lifespan in Dendritic Cells by Preserving Mitochondrial Function

Amiel

Everts

Fritz

et al. 2014

The Journal of Immunology

109

146

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TLR-mediated activation of dendritic cells (DCs) is associated with a metabolic transition in which mitochondrial oxidative phosphorylation is inhibited by endogenously synthesized NO and the cells become committed to glucose and aerobic glycolysis for survival. We show that inhibition of mechanistic target of rapamycin (mTOR) extends the lifespan of TLR-activated DCs by inhibiting the induction of NO production, thereby allowing the cells to continue to use their mitochondria to generate ATP, and allowing them the flexibility to use fatty acids or glucose as nutrients to fuel core metabolism. These data provide novel mechanistic insights into how mTOR modulates DC metabolism and cellular longevity following TLR activation and provide an explanation for previous findings that mTOR inhibition enhances the efficacy of DCs in autologous vaccination.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Target of Rapamycin Inhibition Extends Cellular Lifespan in Dendritic Cells by Preserving Mitochondrial Function

Amiel

Everts

Fritz

et al. 2014

The Journal of Immunology

109

146

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“…The efficiency of clopohosomes to deplete macrophages was confirmed by flow cytometry analysis (data not shown). In some studies, a selective iNOS inhibitor, N6-(1-iminoethyl)-L-lysine, dihydrochloride (14) (L-NIL; Cayman Chemical Company, Ann Arbor, MI) was injected ip.6 mg/kg for the first dose and then 3 mg/kg twice daily or PBS were injected into animals during the time of the experiment.…”

Section: Methodsmentioning

confidence: 99%

Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity

Suwanpradid

Shih

Pontius

et al. 2017

The Journal of Immunology

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The innate immune components that modulate allergic contact hypersensitivity (CHS) responses are poorly defined. Using human skin from contact dermatitis patients and a mouse model of CHS, we find that hapten allergens disrupt the Arginase1 (Arg1) and inducible nitric oxide synthase (iNOS or Nos2) dynamic in monocytes/macrophages, which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in macrophages develop increased CHS characterized by elevated ear thickening, monocytes/macrophage-dominated dermal inflammation, and increased iNOS and IL-6 expression compared to control mice. Treatment of Arg1flox/flox; LysMCre+/− mice with a selective NOS inhibitor or knockout of iNOS significantly ameliorated CHS. Our findings suggest a critical role for Arg1 in monocytes/macrophages in suppressing CHS through dampening Nos2 expression. These results may support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis.

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“…27 Endogenously produced NO has been shown to affect the microbicidal properties, 11 activation, 28 migration, 29 and T cellpriming capacities 30 of DCs. However, little is known about the effects of NO on DC metabolism.…”

Section: No-driven Metabolic Changes In Dendritic Cells 1427mentioning

confidence: 99%

Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

Everts

Amiel

Windt

et al. 2012

Blood

476

568

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TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte-derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte-derived DCs. (Blood. 2012;120(7):1422-1431) IntroductionDendritic cells (DCs) express TLRs that allow them to detect and respond to pathogen-derived molecules. 1,2 In response to TLR agonists, DCs transition from a resting state to an activated state through a process that that involves the induction of expression of genes encoding a broad array of proteins such as cytokines, chemokines, and costimulatory molecules. 3 Activated DCs play a central role in orchestrating the development of immune responses.Recently, we showed that after exposure to TLR agonists, DCs undergo a striking metabolic transition evident as a pronounced increase in the glycolytic rate. 4 This is highly reminiscent of Warburg metabolism, 5 in which tumor cells preferentially use glycolysis rather than catabolic mitochondrial pathways to conserve and generate metabolic resources to meet the demands of cellular proliferation while still producing sufficient ATP to permit these processes to occur. 6,7 Moreover, the increase in glycolytic rate in DCs was found to be dependent on the PI3K/Akt pathway, 4 which is one of the most commonly mutated signaling pathways in tumors. 8 We reasoned that glycolysis could serve essentially the same purpose in active DCs as it is thought to do in tumors. 4 This view was supported by the fact that glucose restriction inhibits severely the activation and life span of DCs exposed to TLR agonists. 4 However, unlike in most cancers, which continue to consume oxygen at rates comparable to normal tissues despite increased glycolytic rates, 9 activated DCs use significantly less oxygen than do resting DCs. 4 Thus far, the molecular mechanisms underlying mitochondrial impairment in activated DCs, and the metabolic consequences of the loss of mitochondrial function, remain unclear.To address these issues, we have in the present study, undertaken a detailed analysis of mitochondrial function in DCs after TLR stimulation. Using extracellular flux analysis to measure changes in oxygen consumption in real time, we found that 6 hours after stimulation, mitochondrial oxygen consumption was progressively lost due to the ...

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Inducible Nitric Oxide Synthase Downmodulates Contact Hypersensitivity by Suppressing Dendritic Cell Migration and Survival

Cited by 14 publications

References 32 publications

Mechanistic Target of Rapamycin Inhibition Extends Cellular Lifespan in Dendritic Cells by Preserving Mitochondrial Function

Mechanistic Target of Rapamycin Inhibition Extends Cellular Lifespan in Dendritic Cells by Preserving Mitochondrial Function

Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity

Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

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