oxidative stress and treg and th17 dysfunction in systemic lupus

Review ArticleOxidative Stress and Treg and Th17 Dysfunction inSystemic Lupus Erythematosus

Ji Yang1 Xue Yang23 Hejian Zou23 and Ming Li1

1Department of Dermatology Zhongshan Hospital Fudan University Shanghai 200032 China2Division of Rheumatology Huashan Hospital Fudan University Shanghai 200040 China3Institute of Rheumatology Immunology and Allergy Fudan University Shanghai 200040 China

Correspondence should be addressed to Hejian Zou hjzoufudaneducn and Ming Li limingzs-hospitalshcn

Received 23 March 2016 Revised 15 May 2016 Accepted 23 May 2016

Academic Editor Gregory Durand

Copyright copy 2016 Ji Yang et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organ systems The pathogenic mechanismsthat cause SLE remain unclear however it is well recognized that the immune balance is disturbed and that this imbalancecontributes to the autoimmune symptoms of SLE Oxidative stress represents an imbalance between the production andmanifestation of reactive oxygen species and the ability of the biological system to readily detoxify the reactive intermediates orto repair the resulting damage In humans oxidative stress is involved in many diseases including atherosclerosis myocardialinfarction and autoimmune diseases Numerous studies have confirmed that oxidative stress plays an important role in thepathogenesis of SLE This review mainly focuses on the recent research advances with respect to oxidative stress and regulatoryT (Treg)helper T 17 (Th17) cell dysfunction in the pathogenesis of SLE

1 Introduction

Systemic lupus erythematosus (SLE) develops following anencounter by genetically predisposed people to environmen-tal agents such as ultraviolet light (UV) infections and ciga-rette smoke that cause oxidative stress but how this oxidativedamage modifies the immune system to induce lupus flaresremains unknown [1ndash3] Activation proliferation or death ofcells of the immune system is dependent on the productionof reactive oxygen intermediates (ROI) and ATP synthesisin the mitochondria [4] Recent studies demonstrated thatmitochondrial dysfunction in T cells promotes the release ofhighly diffusible inflammatory lipid hydroperoxides whichtransfer oxidative stress to other intracellular organellesand through the bloodstream [5ndash7] T lymphocytes of SLEpatients exhibit persistent mitochondrial hyperpolarization(MHP) cytoplasmic alkalinization increased ROI produc-tion and diminished levels of intracellular glutathione [4 7ndash10] Increased production of nitric oxide has been identifiedas a cause of MHP and increased mitochondrial biogenesis

oxidative stress then affects signaling through the T cellreceptor (TCR) [4]

In T cells from SLE patients and animal models of thedisease themain intracellular antioxidant glutathione is con-sumed and oxidized [11 12] Reversal of glutathione depletionby application of its amino acid precursor N-acetylcysteinedecreases disease activity in lupus-prone mice [7 11 13]Doherty and colleagues showed that O

2consumption in the

peripheral blood lymphocytes (PBL) of SLE patients wasincreased Furthermore SLE PBL consumed more O

2upon

in-chamber T cell activation and N-acetylcysteine dimin-ished O

2consumption [14]These data indicate that SLE PBL

exhibit increased O2consumption that is inhibited by N-

acetylcysteine which may have therapeutic efficacy throughreducing oxidative stress in SLE [14] A clinical researchshowed that treatment combined with N-acetylcysteine andhydroxychloroquine an antimalarial drug with ability toreduce the sensitivity of skin to UV exposure could inhibitoxidative stress status and relieved the lupus activity [15]

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 2526174 9 pageshttpdxdoiorg10115520162526174

2 Oxidative Medicine and Cellular Longevity

Together these data indicate that oxidative stress plays a keyrole in T cell dysfunction and the progression of lupus

2 Oxidative Stress and Treg Cells

Regulatory T (Treg) cells are capable of modulating thefunction of effector T cells maintaining immunologic home-ostasis and preventing autoimmunity [16] Circulating Tregnumbers decrease during disease flares in SLE patients andthe immune suppressive function of Treg cells in lupus isimpaired [17ndash21] The underlying reasons for this decreasein the number and function of Treg cells in SLE are notclear Foxp3 is essential for the development and functionof CD4+CD25+ regulatory T cells [22] and induction of thetranscription factor Foxp3 can transform CD4+CD25minus naıveT cells into CD4+CD25+ regulatory T cells [22] In additionTreg cell activity can be induced in the peripheral immunesystem by the conversion of naıve CD4+Foxp3minus T cells intoFoxp3+ T cells via transforming growth factor-beta (TGF-120573)[23 24] In addition interleukin- (IL-) 6 is a key cytokinethat inhibits Foxp3 expression during Treg cell differentiation[24] Previous studies have demonstrated that hyperoxia-induced stress and oxidative damage lead to an increase in IL-6 and concordantly increased production of IL-6 has beendocumented in SLE patients [24 25] Thus oxidative stress-induced increased production of IL-6 may be the primaryreason for the decrease in Treg cells in SLE patients

Activation of the mammalian target of rapamycin(mTOR) has recently emerged as a key sensor of MHP andmediator of enhancedCa2+ flux in lupusT cells [4 26]mTORis a ubiquitous serinethreonine kinase that is a criticalintegrator of environmental stimuli and regulates signalingin T cells to influence homeostasis differentiation andactivation [27 28] The effects of mTOR are cell type-specificand are elicited in response to stimulation by growth factorshormones and cytokines as well as in response to internaland external metabolic products [29] Recent observationshave demonstrated thatMHPand enhancedCa2+ fluxing inTcells contribute to injury in lupus [30 31] In T cells increasedproduction of nitric oxide and MHP were identified asmetabolic checkpoints upstream of mTOR activation [31 32]Additionally mTOR controls the expression of the TCR-associated signaling protein CD4 and through increasedexpression of the endosome recycling regulator HRES-1Rab4 mTORmediates enhanced Ca2+ flux skews the expres-sion of tyrosine kinases in T cells and blocks the expression ofFoxp3 and the expansion of regulatory cells [31 32]

Recently additional work further demonstrated thatmTOR controls the differentiation and functions of Treg cellssuggesting that its activity could be targeted to modulateTreg responses [27 29] Specifically mTOR was identifiedas a component of two interacting complexes mTORC1 andmTORC2 that regulate T cell lineage differentiation [33 34]Activation of mTOR delivers an obligatory signal for theproper activation and differentiation of effector CD4+ T cellswhereas in Treg cell differentiation the Akt-mTOR axis isa negative regulator of Treg cell [29 33 34] SpecificallymTORC1 drives the proinflammatory lymphocyte subset

expansion of T helper 1 (Th1) and T helper 17 (Th17) cellsmTORC2 favors the expansion of T follicular helper (Tfh)cells [35] which promote B cell activation and autoantibodyproduction [29] Both mTORC1 and mTORC2 inhibit thedevelopment of CD4+CD25+Foxp3+ Treg cells [29]

Furthermore mTORC1 activity is high in human andmurine Tregs [27 29 33 36] and this activity restrains TCRandor IL-2 stimulation-induced proliferation of Treg cells invitro [36] Rapamycin a lipophilic macrolide antibiotic thatregulates mitochondrial transmembrane potential and Ca2+flux has been used safely and effectively to treat lupus [31 3237] Rapamycin inhibitsmTORC1 in Tregs and then promotesTreg cell expansion in SLE patients [38] The effectiveness ofrapamycin in murine and human SLE further supports thenotion that mTOR is indeed a key mediator of autoimmunityin SLETherefore understanding themechanisms underlyingthe persistent MHP that leads to mTOR activation andenhanced Ca2+ flux is fundamental to understanding thepathogenesis of lupus [32]These findings suggest thatmTORblockade may increase life expectancy via treatment andprevention of SLE inflammatory injury [7 13 29]

Another T cell biology regulator is leptin which is ahormone derived from adipocytes Leptin is closely relatedto adipokines which are associated with oxidative stress andare reported to be overproduced in SLE patients [39 40]Previous data indicate that leptin signaling modulates T cellproliferation and preferential differentiation of Th1 cells overTh2 cells [41ndash43] Recently high levels of leptin receptorwere detected in Treg cells Interestingly leptin was foundto restrain Treg cell proliferation as neutralization of leptinenhanced TCR and IL-2-induced Treg cell expansion [43ndash45] Leptin receptor-deficient Treg cells also have increasedproliferative responses linked to reduced mTOR activation[36 41 46 47] Thus leptin sensing in Tregs is critical fordampening excessive mTOR activation and driving Treg pro-liferation [48] Both mTOR inhibition and amino acid depri-vation synergize with TGF-120573 to augment Foxp3 expression invitro [27 47 48] High leptin secretion has been reported inlupus patients and thus this secretion may be one of thekey reasons underlying the induction of mTORC1-meditatedinhibition of Treg cell differentiation as well as proinflamma-tory Th17 cell and other effector T cell expansion in SLE [2749 50] Recent study showed that superoxide production isincreased in all lymphocyte subsets of patients with antiphos-pholipid syndrome (APS) a special type of SLEThe oxidativestress was related to CD4+CD25+Foxp3+ Treg cell depletionin APS patients [51]

These data indicate that oxidative stress may contributeto the depletion of Treg cells in SLE patients suggesting thatantioxidation treatmentmay be an effectivemethod to relievelupus symptoms via improving Treg cell differentiationThusstrategies to enhance the number and function of Treg cellsmay benefit patients with SLE Leptin and mTOR may alsoserve as effective intervention targets to relieve oxidativestress and improve the differentiation of Treg cells in SLE(Figure 1) In addition Chinese herbs or compounds isolatedfrom natural herbs also appear to be promising therapeuticagents for control of the oxidative stress noted in SLE patients

Oxidative Medicine and Cellular Longevity 3

FICZ uarr

AHR

Foxp3

Treg cells

mTORC1

TGF-120573IL-2

Rapamycin

Leptin uarr

IL-6 uarr

Nitric oxide uarrMHP uarrCa2+ flux uarr

Figure 1 Oxidative stress and mTORC1-mediated Treg cell dif-ferentiation TGF-120573 and IL-2 can induce CD4+Foxp3+ Treg cellsexpansion and overproduction of IL-6 in SLE patients inhibitsFoxp3 expression during Treg cell differentiation Oxidative stresscan promote increased production of leptin nitric oxide MHPand enhanced Ca2+ flux in lupus T cells which can result inoverexpression of mTORC1 and then inhibit the development ofCD4+CD25+Foxp3+ Treg cells UV exposure-mediated increasedproduction of FICZ can activate AHR signaling pathway and theninhibit Foxp3 expression in SLE Rapamycin can inhibit mTORC1 inTregs and then it promoted Treg cell expansion

3 Oxidative Stress and Th17 Abnormality

The Th17 lineage is a lineage of effector CD4+ T cells and ischaracterized by the production of IL-17 [52 53] Expan-sion of Th17 cells has been included in a growing list ofautoimmune disorders [53 54] Our studies as well as thoseof others have demonstrated that Th17 cells play a keyrole in the pathogenesis of SLE [17 18 54] Environmentalfactors including exposure to UV radiation infection envi-ronmental pollution and emotional changes are believed tocontribute to the increased prevalence of SLE and to aggravatelupus activity [55] UV radiation exposure is among theenvironmental factors that have been studied the most withrespect to association with SLE [55 56] While experimentalstudies show a significant immunomodulatory role for UVradiation epidemiologic data describe its role in triggeringSLE onset and patient deterioration [55ndash59] To date weunderstand that both UVB and UVA play a role in thepathogenesis of lupus erythematosus [58] In the epidermisUV radiation inducesDNAdamage exposes nuclear antigensand photoinduced neoantigens at the cell surface leads toan accumulation of apoptotic material and induces severalproinflammatory cytokines [58] In the dermis UV radi-ation triggers skin inflammatory cell infiltration [58] UVradiation-induced signaling involves two major pathwaysone that is initiated through the generation of DNA photo-products in the nucleus and one that occurs independently

of DNA damage and is characterized by cell surface receptoractivation [58]

The aryl hydrocarbon receptor (AHR) is a ligand-depen-dent transcription factor best known for mediating thetoxicity of dioxin [60] AHRwas discovered as a specific bind-ing site for 2378-tetrachlorodibenzo-p-dioxin (TCDD) anenvironmental toxin [61] AHR detects not only pollutantsbut many other environmental compounds as well suchas indoles and flavonoids of dietary origin and tryptophanmetabolites that are generated by exposure to UV light orby bacteria of the intestinal microflora [62] AHR expressionis highly upregulated in Th17 cells following activation byboth TGF-120573 and IL-6 and promotes IL-22 production andenhances Th17 development [63] The ligand-activated tran-scription factor AHR is identified as a regulator of Treg andTh17 cell differentiation and plays a key role in both Tregcell development and Th17 cell differentiation [64 65]Intriguingly two different high-affinity ligands for AHR acti-vation TCDD and 6-formylindolo[32-b]carbazole (FICZ)can play different roles in the differentiation of Th17 andTreg cells [64] AHR activation by its ligand TCDD inducesfunctional Treg cells that suppress experimental autoimmuneencephalomyelitis (EAE) [61 64] Conversely AHR activa-tion by FICZ interferes with Treg cell development promotesTh17 cell differentiation and aggravates the severity of EAE inmice [64] Thus AHR regulates both Treg and Th17 cell dif-ferentiation in a ligand-specific fashion constituting a uniquetarget for therapeutic immunomodulation Dorgham andcolleagues demonstrated that propranolol a potential lupus-inducing drug caused stronger AHR activation in PBMCs ofSLE patients than in those of controls [66] This compoundbehaves like the prototypic AHR ligand FICZ promoting IL-22 IL-8 andCCL2 secretion byT cells andmacrophages [66]These data indicate the AHR activationmay play a key role inthe pathogenesis of SLE

AHR typically resides in the cytoplasm in complex withHsp90 until the binding of its ligand triggers conformationalchanges resulting in an exchange of Hsp90 for the nucleartranslocation component ARNT [64 67] The endogenousAHR ligand FICZ may contribute to adverse physiologi-cal responses evoked by small natural and anthropogenicmolecules as well as by oxidative stress and light [68] FICZ isformed from tryptophan in aqueous solutions upon exposureto UV and visible light and also in human skin cells exposedin vitro to UVB light [68 69] UVB hydrogen peroxide(H2O2) and 31015840-methoxy-41015840-nitroflavone (MNF) promote

the generation of FICZ and thereby give rise to prolongedAHR signaling [70 71] Intracellular formation of FICZinteractedwithAHRand then results in translocation ofAHRinto the nucleus and induction of CYP1A1 gene expressionand elicits inflammation enlargement [64] UVB radiationtriggers AHR signaling by generating FICZ [62] and UVBirradiation-induced deterioration in SLE might be caused bythe production of FICZ AHR activation and subsequentTh17 cell expansion [66 69]Thus AHR-FICZ signaling is anintegral part of the UVB stress response and the AHR maytherefore represent a target for therapeutic intervention inlupus


UV exposure uarr

FICZ uarr

H2O2 uarr

AHR

AHR

AHR

Hsp90

Hsp90 ARNT

CYP1A1 and so forthFICZ

Th17 cells

IL-17IL-21IL-22

Leptin uarr

TGF-120573IL-6

mTORC1uarr

Figure 2 Oxidative stress and AHR-mediatedTh17 cell differentiation Increased UV exposure H2O2 and leptin can promote the generation

of FICZ a natural ligand of AHR AHR usually resides in the cytoplasm in complex with Hsp90 Interaction between AHR and ligands FICZtriggers conformational changes resulting in an exchange of Hsp90 for the nuclear translocation component ARNT and induces target genesexpression such as Cyp1a1 triggeringTh17 cell expansion and IL-17 IL-21 and IL-22 production Oxidative stress can also elicit the activationof mTORC1 which then promotes Th17 cell differentiation and related cytokines production

Based on the above discussion we speculate that in SLEpatients UV exposure can directly induce DNA damagegeneration of DNA photoproducts and apoptotic materialwhich consequently induces B cell activation and autoan-tibody production Furthermore UV exposure elicits AHRactivation and the generation of FICZ which is a high-affinityligand for AHR activation and can further promote the differ-entiation of the Th17 cell population thereby worsening theseverity of lupus (Figure 2) Furthermore the expansion ofTh17 cells and overproduction of IL-17 may further aggravatelupus injury as IL-17 can amplify the immune response byinducing the local production of chemokines and cytokinesrecruiting neutrophils and monocytes augmenting the pro-duction of autoantibodies and aggravating the inflammationand damage of target organs such as the kidney in SLE

Enhanced Ca2+ flux has been a hallmark characteris-tic in SLE patients and recent studies have demonstratedthe involvement of calciumcalmodulin-dependent proteinkinase IV (CaMK4) in the pathogenesis of SLE [72 73]CaMK4 can facilitate the recruitment of IL-17-producing cellsto kidney of antiglomerular basement membrane antibody-induced glomerulonephritis (AIGN) mice and Camk4-deficientmice displayed less glomerular injury and decreasedinfiltration by IL-17-producing CD4 T cells in kidney [74] Inaddition inhibition of CaMK4 could reduce IL-17 transcrip-tion through reduced activation of the AKTmTOR pathway

which is known to enhance retinoic acid receptor-relatedorphan receptor- (ROR120574t-) mediated Th17 cell differentia-tion Importantly silencing CaMK4 in T cells from patientswith SLE inhibited Th17 differentiation Collectively thesedata suggest that CaMK4 inhibition has potential as a thera-peutic strategy for Th17-related SLE patients [75]

mTOR is identified as a component of two interactingcomplexes mTORC1 and mTORC2 that regulate T cell lin-eage specification differentiation [29] Oxidative stress in SLEcan induce the activation of mTORC1 TORC1 signaling pos-itively promotes Th17 cell differentiation via multiple mech-anisms including the regulation of HIF-1 expression STAT3phosphorylation and the nuclear translocation of ROR120574t [3576] Both mTORC1 and mTORC2 inhibit the developmentof Treg cells mTORC2 promotes the expansion of Tfh andTh2 cells [29 35] In this regard antioxidant therapy andmTOR blockade promise to relieve the inflammatory injuryvia regulating immune balance in SLE (Figure 3)

4 Antioxidant Therapy in SLE

Our previous findings demonstrated that baicalin acompound isolated from a Chinese herb increasedCD4+CD25+Foxp3+ Treg cell differentiation in vitro andthat baicalin treatment protected lupus-prone MRLlpr miceagainst nephritis and improved the Treg cells in vivo [77 78]


Oxidative stress uarr

Th17 cellsTreg cells

Foxp3

mTORC1 mTORC2

STAT3

ROR120574t

Antioxidanttherapy

IL-17IL-21

TGF-120573IL-10

Figure 3 Oxidative stress and mTOR-mediated Th17Treg imbalance in SLE patients Oxidative stress can elicit the activation of mTORC1and mTORC2 Both mTORC1 and mTORC2 can then inhibit Foxp3-mediated Treg cell development mTORC1 promotes the expansion ofTh17 cells via activating STAT3 and ROR120574t And antioxidant therapy and mTOR blockade might be useful for regulating Th17 and Treg cellimmune balance in SLE patients

Treg Treg TregTh17 Th17 Th17

Th17

Th17

Normal stage

Oxidative stress

SLE patient

Healthy person

Figure 4 Oxidative stress and Th17Treg imbalance in SLE patients Under the normal stage Th17 cells and Treg cells stay in a dynamicimmune balance Increased oxidative stress was induced in SLE patients which can further induce and expand the proinflammatory Th17cells and inhibit the anti-inflammatory Treg cell differentiation and aggravate autoimmune injuries

Currently baicalin is considered to be a potent antioxidativestress drug [79 80] Therefore we hypothesized that baicalinmay promote the differentiation of Treg cells via antioxidativestress effects however we have yet to test this hypothesisdirectly Hydroxychloroquine a drug often used in thetreatment of SLE with ability to reduce sensitivity of theskin to UV exposure can inhibit Th17 cell expansion andIL-17 production [81] Our research group is working on theunderlyingmechanismwhether hydroxychloroquine inhibitsTh17 cell expansion via regulating AHR-FICZ signalingpathway in SLE patients Resveratrol a powerful antioxidantpossesses protective effects in pristane-induced lupus mousemodel 82 Although resveratrol can inhibit mTOR pathway[82 83] further study should be performed on whetherresveratrol relieves lupus injury via inhibiting mTOR-mediated Th17 cell expansion Antroquinonol a purifiedcompound and major effective component of Antrodiacamphorata with antioxidant activities has been provedto prevent the transformation of mild lupus nephritis intohigher-grade nephritis in a murine lupus model [84]

Antroquinonol inhibited production of reactive oxygenspecies and nitric oxide and enhanced Treg cell suppressionvia increasing activation of nuclear factor E2-related factor2 (Nrf2) which is referred to as the ldquomaster regulatorrdquo ofthe antioxidant response [84] Epigallocatechin-3-gallatethe major bioactive polyphenol present in green tea withantioxidant and free radical scavenging activities has beenproved to prevent lupus nephritis development in micevia reducing proteinuria renal function impairment andimproving renal injury [85] Epigallocatechin-3-gallatehas prophylactic effects on lupus nephritis that are highlyassociated with its effects of enhancing the Nrf2 antioxidantsignaling pathway decreasing renal NLRP3 inflammasomeactivation and increasing systemic Treg cell activity [85]A randomized double-blind placebo-controlled study hasproved that N-acetylcysteine reduces disease activity byblocking mTOR pathway in T cells from systemic lupuserythematosus patients N-acetylcysteine could reverseexpansion of CD4minusCD8minus T cells stimulate Foxp3 expressionin CD4+CD25+ T cells and reduce anti-DNA production


[13] Altogether these data suggest that antioxidant drugmight be promising therapeutic methods for the treatmentof SLE and the specific therapeutic mechanism needs to befurther studied

Taken together these data show that oxidative stress playsa key role in the pathogenesis of SLE Oxidative stress caninduce and aggravate SLE by linking environmental stimu-lation with immune imbalance Oxidative stress contributedthe Th17Treg imbalance in SLE patients Under the normalstage Th17 cells and Treg cells stay in a dynamic immunebalance while oxidative stress was induced in SLE patientswhich can further induce and expand the proinflammatoryTh17 cells expansion and inhibit the anti-inflammatory Tregcell differentiation and aggravate autoimmune injuries (Fig-ure 4) Above we described the receptors and transcriptionfactors that may offer key targets for the regulation ofoxidative stress and immunity and thus for the treatment ofSLE

Disclosure

Ji Yang and Xue Yang are co-first authors

Competing Interests

The authors declare that there are no competing interestsregarding the publication of this paper

Authorsrsquo Contributions

Ji Yang and Xue Yang contributed equally to this work

Acknowledgments

This work was supported by grants from the National Nat-ural Science Foundation of China (nos 81472874 8140134681373213) Medical Guide Project from Shanghai Munic-ipal Science and Technology (134119a8400) CultivationPlan of Young Doctor of Shanghai (2014) and Outstand-ing Talent Plan of Zhongshan Hospital Fudan University(2015ZSYXGG13)

References

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[2] FM Strickland Y Li K Johnson Z Sun and B C RichardsonldquoCD4+ T cells epigenetically modified by oxidative stress causelupus-like autoimmunity in micerdquo Journal of Autoimmunityvol 62 pp 75ndash80 2015

[3] G Davı and A Falco ldquoOxidant stress inflammation andatherogenesisrdquo Lupus vol 14 no 9 pp 760ndash764 2005

[4] A Perl R Hanczko and E Doherty ldquoAssessment of mito-chondrial dysfunction in lymphocytes of patients with systemiclupus erythematosusrdquo Methods in Molecular Biology vol 900pp 61ndash89 2012

[5] A Perl P Gergely Jr andK Banki ldquoMitochondrial dysfunctionin T cells of patients with systemic lupus erythematosusrdquo

International Reviews of Immunology vol 23 no 3-4 pp 293ndash313 2004

[6] P Gergely Jr C Grossman B Niland et al ldquoMitochondrialhyperpolarization and ATP depletion in patients with systemiclupus erythematosusrdquo Arthritis and Rheumatism vol 46 no 1pp 175ndash190 2002

[7] A Perl ldquoOxidative stress in the pathology and treatment ofsystemic lupus erythematosusrdquo Nature Reviews Rheumatologyvol 9 no 11 pp 674ndash686 2013

[8] B D Leishangthem A Sharma and A Bhatnagar ldquoRole ofaltered mitochondria functions in the pathogenesis of systemiclupus erythematosusrdquo Lupus vol 25 no 3 pp 272ndash281 2016

[9] P Gergely Jr B Niland N Gonchoroff R Pullmann Jr P EPhillips and A Perl ldquoPersistent mitochondrial hyperpolariza-tion increased reactive oxygen intermediate production andcytoplasmic alkalinization characterize altered IL-10 signalingin patients with systemic lupus erythematosusrdquo The Journal ofImmunology vol 169 no 2 pp 1092ndash1101 2002

[10] A Perl G Nagy P Gergely F Puskas Y Qian and K BankildquoApoptosis and mitochondrial dysfunction in lymphocytesof patients with systemic lupus erythematosusrdquo Methods inMolecular Medicine vol 102 pp 87ndash114 2004

[11] A Perl R Hanczko Z-W Lai et al ldquoComprehensivemetabolome analyses reveal N-acetylcysteine-responsive accu-mulation of kynurenine in systemic lupus erythematosusimplications for activation of the mechanistic target ofrapamycinrdquoMetabolomics vol 11 no 5 pp 1157ndash1174 2015

[12] Q Zhang DQ Ye G P Chen andY Zheng ldquoOxidative proteindamage and antioxidant status in systemic lupus erythemato-susrdquo Clinical and Experimental Dermatology vol 35 no 3 pp287ndash294 2010

[13] Z-W Lai R Hanczko E Bonilla et al ldquoN-acetylcysteinereduces disease activity by blocking mammalian target of rapa-mycin in T cells from systemic lupus erythematosus patientsa randomized double-blind placebo-controlled trialrdquo Arthritisamp Rheumatism vol 64 no 9 pp 2937ndash2946 2012

[14] E Doherty Z Oaks and A Perl ldquoIncreased mitochondrialelectron transport chain activity at complex i is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupuserythematosusrdquoAntioxidants and Redox Signaling vol 21 no 1pp 56ndash65 2014

[15] M Li W Gao J Ma Y Zhu and X Li ldquoEarly-stage lupusnephritis treated with N-acetylcysteine a report of two casesrdquoExperimental and Therapeutic Medicine vol 10 no 2 pp 689ndash692 2015

[16] E M Shevach ldquoRegulatory T cells in autoimmmunityrdquo AnnualReview of Immunology vol 18 pp 423ndash449 2000

[17] J Yang Y Chu X Yang et al ldquoTh17 and natural treg cell popu-lation dynamics in systemic lupus erythematosusrdquoArthritis andRheumatism vol 60 no 5 pp 1472ndash1483 2009

[18] J Yang X Yang H Zou Y Chu and M Li ldquoRecovery of theimmune balance betweenTh17 and regulatory T cells as a treat-ment for systemic lupus erythematosusrdquo Rheumatology vol 50no 8 pp 1366ndash1372 2011

[19] R K Venigalla T Tretter S Krienke et al ldquoReducedCD4+CD25- T cell sensitivity to the suppressive function ofCD4+CD25highCD127 -low regulatory T cells in patientswith active systemic lupus erythematosusrdquoArthritis amp Rheuma-tology vol 58 pp 2120ndash2130 2008


[20] M V Legorreta-Haquet K Chavez-Rueda L Chavez-Sanchezet al ldquoFunction of Treg cells decreased in patients with systemiclupus erythematosus due to the effect of prolactinrdquo Medicinevol 95 no 5 Article ID e2384 2016

[21] K Ohl and K Tenbrock ldquoRegulatory T cells in systemic lupuserythematosusrdquo European Journal of Immunology vol 45 no 2pp 344ndash355 2015

[22] J D Fontenot M A Gavin and A Y Rudensky ldquoFoxp3 pro-grams the development and function ofCD4+CD25+ regulatoryT cellsrdquo Nature Immunology vol 4 no 4 pp 330ndash336 2003

[23] F S Regateiro D Howie S P Cobbold and H WaldmannldquoTGF-120573 in transplantation tolerancerdquo Current Opinion inImmunology vol 23 no 5 pp 660ndash669 2011

[24] S Sakaguchi and N Sakaguchi ldquoRegulatory T cells in immuno-logic self-tolerance and autoimmune diseaserdquo InternationalReviews of Immunology vol 24 no 3-4 pp 211ndash226 2005

[25] Y X Cui CW Fu F Jiang L X Ye andWMeng ldquoAssociationof the interleukin-6 polymorphismswith systemic lupus erythe-matosus a meta-analysisrdquo Lupus vol 24 no 12 pp 1308ndash13172015

[26] D Fernandez and A Perl ldquomTOR signaling a central pathwayto pathogenesis in systemic lupus erythematosusrdquo Discoverymedicine vol 9 no 46 pp 173ndash178 2010

[27] N M Chapman and H Chi ldquomTOR signaling Tregs andimmune modulationrdquo Immunotherapy vol 6 no 12 pp 1295ndash1311 2014

[28] Y Liu D-T Zhang and X-G Liu ldquomTOR signaling in T cellimmunity and autoimmunityrdquo International Reviews of Immu-nology vol 34 no 1 pp 50ndash66 2015

[29] A Perl ldquoActivation of mTOR (mechanistic target of rapamycin)in rheumatic diseasesrdquo Nature Reviews Rheumatology vol 12no 3 pp 169ndash182 2015

[30] G Nagy M Barcza N Gonchoroff P E Phillips and A PerlldquoNitric oxide-dependent mitochondrial biogenesis generatesCa2+ signaling profile of lupus T cellsrdquoThe Journal of Immunol-ogy vol 173 no 6 pp 3676ndash3683 2004

[31] A Perl ldquoSystems biology of lupus mapping the impact ofgenomic and environmental factors on gene expression sig-natures cellular signaling metabolic pathways hormonal andcytokine imbalance and selecting targets for treatmentrdquoAutoimmunity vol 43 no 1 pp 32ndash47 2010

[32] A Perl D R Fernandez T Telarico E Doherty L Francisand P E Phillips ldquoT-cell and B-cell signaling biomarkers andtreatment targets in lupusrdquo Current Opinion in Rheumatologyvol 21 no 5 pp 454ndash464 2009

[33] H Zeng K Yang C Cloer G Neale P Vogel and H ChildquoMTORC1 couples immune signals and metabolic program-ming to establish T reg-cell functionrdquoNature vol 499 no 7459pp 485ndash490 2013

[34] A Perl ldquomTOR activation is a biomarker and a central pathwayto autoimmune disorders cancer obesity and agingrdquo Annals ofthe New York Academy of Sciences vol 1346 no 1 pp 33ndash442015

[35] GMDelgoffe K N Pollizzi A TWaickman et al ldquoThe kinasemTOR regulates the differentiation of helper T cells throughthe selective activation of signaling bymTORC1 andmTORC2rdquoNature Immunology vol 12 no 4 pp 295ndash303 2011

[36] C Procaccini V De Rosa M Galgani et al ldquoAn oscillatoryswitch in mTOR kinase activity sets regulatory T cell respon-sivenessrdquo Immunity vol 33 no 6 pp 929ndash941 2010

[37] D Fernandez E Bonilla N Mirza B Niland and A PerlldquoRapamycin reduces disease activity and normalizes T cellactivation-induced calcium fluxing in patients with systemiclupus erythematosusrdquo Arthritis and Rheumatism vol 54 no 9pp 2983ndash2988 2006

[38] H Kato andA Perl ldquoMechanistic target of rapamycin complex 1expandsTh17 and IL-4+ CD4minusCD8minus double-negativeT cells andcontracts regulatory T cells in systemic lupus erythematosusrdquoThe Journal of Immunology vol 192 no 9 pp 4134ndash4144 2014

[39] X Zhang E Lindwall C Gauthier et al ldquoCirculatingCXCR5+CD4+helper T cells in systemic lupus erythematosuspatients share phenotypic properties with germinal center fol-licular helper T cells and promote antibody productionrdquo Lupusvol 24 no 9 pp 909ndash917 2015

[40] C P Chung A G Long J F Solus et al ldquoAdipocytokines insystemic lupus erythematosus relationship to inflammationinsulin resistance and coronary atherosclerosisrdquo Lupus vol 18no 9 pp 799ndash806 2009

[41] C Procaccini V De Rosa M Galgani et al ldquoLeptin-inducedmTOR activation defines a specific molecular and transcrip-tional signature controlling CD4+ effector T cell responsesrdquoTheJournal of Immunology vol 189 no 6 pp 2941ndash2953 2012

[42] G M Lord G Matarese J K Howard R J Baker S RBloom and R I Lechler ldquoLeptin modulates the T-cell immuneresponse and reverses starvation-induced immunosuppres-sionrdquo Nature vol 394 no 6696 pp 897ndash901 1998

[43] G Amarilyo N Iikuni F-D Shi A Liu G Matarese and ALa Cava ldquoLeptin promotes lupus T-cell autoimmunityrdquo ClinicalImmunology vol 149 pp 530ndash533 2013

[44] V De Rosa C Procaccini G Calı et al ldquoA key role of leptin inthe control of regulatory T cell proliferationrdquo Immunity vol 26no 2 pp 241ndash255 2007

[45] D Margiotta L Navarini M Vadacca et al ldquoRelationshipbetween leptin and regulatory T cells in systemic lupus erythe-matosus preliminary resultsrdquo European Review for Medical andPharmacological Sciences vol 20 no 4 pp 636ndash641 2016

[46] S Taleb O Herbin H Ait-Oufella et al ldquoDefective leptinleptin receptor signaling improves regulatory T cell immuneresponse and protects mice from atherosclerosisrdquo Arterioscle-rosis Thrombosis and Vascular Biology vol 27 no 12 pp 2691ndash2698 2007

[47] H Zeng and H Chi ldquoThe interplay between regulatory T cellsand metabolism in immune regulationrdquo OncoImmunology vol2 no 11 Article ID e26586 2013

[48] J AMaciolek J Alex Pasternak andH LWilson ldquoMetabolismof activated T lymphocytesrdquo Current Opinion in Immunologyvol 27 no 1 pp 60ndash74 2014

[49] Y Fujita T Fujii T Mimori et al ldquoDeficient leptin signalingameliorates systemic lupus erythematosus lesions in MRLMp-119865119886119904119897119901119903micerdquoThe Journal of Immunology vol 192 no 3 pp 979ndash984 2014

[50] Y Yu Y Liu F-D Shi H Zou G Matarese and A La CavaldquoCutting edge leptin-induced ROR120574t expression in CD4+ Tcells promotes Th17 responses in systemic lupus erythemato-susrdquoThe Journal of Immunology vol 190 no 7 pp 3054ndash30582013

[51] Z-W Lai I Marchena-Mendez and A Perl ldquoOxidative stressand Treg depletion in lupus patients with anti-phospholipidsyndromerdquo Clinical Immunology vol 158 no 2 pp 148ndash1522015


[52] H Park Z Li X O Yang et al ldquoA distinct lineage of CD4 Tcells regulates tissue inflammation by producing interleukin 17rdquoNature Immunology vol 6 no 11 pp 1133ndash1141 2005

[53] P R Burkett G M Zu Horste and V K Kuchroo ldquoPouringfuel on the fireTh17 cells the environment and autoimmunityrdquoJournal of Clinical Investigation vol 125 no 6 pp 2211ndash22192015

[54] D Li B Guo HWu L Tan C Chang and Q Lu ldquoInterleukin-17 in systemic lupus erythematosus a comprehensive reviewrdquoAutoimmunity vol 48 no 6 pp 353ndash361 2015

[55] M Barbhaiya andKH Costenbader ldquoUltraviolet radiation andsystemic lupus erythematosusrdquo Lupus vol 23 no 6 pp 588ndash595 2014

[56] A Kuhn J Wenzel and H Weyd ldquoPhotosensitivity apoptosisand cytokines in the pathogenesis of lupus erythematosus acritical reviewrdquo Clinical Reviews in Allergy amp Immunology vol47 no 2 pp 148ndash162 2014

[57] L Fenton R Dawe S Ibbotson J Ferguson S Silburn andH Moseley ldquoImpact assessment of energy-efficient lightingin patients with lupus erythematosus A pilot studyrdquo BritishJournal of Dermatology vol 170 no 3 pp 694ndash698 2014

[58] N Scheinfeld and V A Deleo ldquoPhotosensitivity in lupuserythematosusrdquo Photodermatology Photoimmunology and Pho-tomedicine vol 20 no 5 pp 272ndash279 2004

[59] L I Craciun M DiGiambattista L Schandene R Laub MGoldman and E Dupont ldquoAnti-inflammatory effects of UV-irradiated lymphocytes induction of IL-1Ra upon phagocytosisby monocytemacrophagesrdquo Clinical Immunology vol 114 no3 pp 320ndash326 2005

[60] M Veldhoen K Hirota A M Westendorf et al ldquoThe arylhydrocarbon receptor links TH17-cell-mediated autoimmunityto environmental toxinsrdquoNature vol 453 no 7191 pp 106ndash1092008

[61] C Esser A Rannug and B Stockinger ldquoThe aryl hydrocarbonreceptor in immunityrdquo Trends in Immunology vol 30 no 9 pp447ndash454 2009

[62] B Jux S Kadow S Luecke A Rannug J Krutmann and CEsser ldquoThe aryl hydrocarbon receptormediates UVB radiation-induced skin tanningrdquo Journal of Investigative Dermatology vol131 no 1 pp 203ndash210 2011

[63] M Veldhoen K Hirota J Christensen A OrsquoGarra and BStockinger ldquoNatural agonists for aryl hydrocarbon receptor inculture medium are essential for optimal differentiation ofTh17T cellsrdquo The Journal of Experimental Medicine vol 206 no 1pp 43ndash49 2009

[64] B Stockinger P Di Meglio M Gialitakis and J H DuarteldquoThe aryl hydrocarbon receptor multitasking in the immunesystemrdquo Annual Review of Immunology vol 32 pp 403ndash4322014

[65] F J Quintana A S Basso A H Iglesias et al ldquoControl of Tregand TH17 cell differentiation by the aryl hydrocarbon receptorrdquoNature vol 453 no 7191 pp 65ndash71 2008

[66] K Dorgham Z Amoura C Parizot et al ldquoUltraviolet lightconverts propranolol a nonselective 120573-blocker and potentiallupus-inducing drug into a proinflammatory AhR ligandrdquoEuropean Journal of Immunology vol 45 no 11 pp 3174ndash31872015

[67] N Tsuji K Fukuda Y Nagata et al ldquoThe activationmechanismof the aryl hydrocarbon receptor (AhR) bymolecular chaperoneHSP90rdquo FEBS Open Bio vol 4 pp 796ndash803 2014

[68] E Wincent J Bengtsson A M Bardbori et al ldquoInhibition ofcytochromeP4501-dependent clearance of the endogenous ago-nist FICZ as amechanism for activation of the aryl hydrocarbonreceptorrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 12 pp 4479ndash4484 2012

[69] D N Syed and H Mukhtar ldquoFICZ a messenger of light inhuman skinrdquo Journal of Investigative Dermatology vol 135 no6 pp 1478ndash1481 2015

[70] S Luecke E Wincent M Backlund et al ldquoCytochrome P4501A1 gene regulation by UVB involves crosstalk between the arylhydrocarbon receptor and nuclear factor kappaBrdquo Chemico-Biological Interactions vol 184 pp 466ndash473 2010

[71] A Smirnova E Wincent L Vikstrom Bergander et al ldquoEvi-dence for new light-independent pathways for generation of theendogenous aryl hydrocarbon receptor agonist FICZrdquoChemicalResearch in Toxicology vol 29 no 1 pp 75ndash86 2016

[72] K Ichinose T Ushigusa A Nishino et al ldquoLupus nephritis IgGinduction of calciumcalmodulin-dependent protein kinaseIV expression in podocytes and alteration of their functionrdquoArthritis amp Rheumatology vol 68 no 4 pp 944ndash952 2016

[73] K Ichinose T Rauen Y-T Juang et al ldquoCutting edgecalciumcalmodulin-dependent protein kinase type IV is essen-tial for mesangial cell proliferation and lupus nephritisrdquo TheJournal of Immunology vol 187 no 11 pp 5500ndash5504 2011

[74] T Koga K Otomo M Mizui et al ldquoCaMK4 facilitates therecruitment of IL-17-producing cells to target organs throughthe CCR6CCL20 axis in Th17-driven inflammatory diseasesrdquoArthritis amp Rheumatology vol 68 no 8 pp 1981ndash1988 2016

[75] T Koga C M Hedrich M Mizui et al ldquoCaMK4-dependentactivation of AKTmTOR and CREM-120572 underlies autoim-munity-associated Th17 imbalancerdquo The Journal of ClinicalInvestigation vol 124 no 5 pp 2234ndash2245 2014

[76] S Nagai Y Kurebayashi and S Koyasu ldquoRole of PI3KAkt andmTORcomplexes inTh17 cell differentiationrdquoAnnals of theNewYork Academy of Sciences vol 1280 no 1 pp 30ndash34 2013

[77] J Yang X Yang andM Li ldquoBaicalin a natural compound pro-motes regulatory T cell differentiationrdquo BMC Complementaryand Alternative Medicine vol 12 article 64 2012

[78] J Yang X Yang Y Chu and M Li ldquoIdentification of Baicalinas an immunoregulatory compound by controlling TH17 celldifferentiationrdquo PLoS ONE vol 6 no 2 Article ID e17164 2011

[79] M Lin L Li Y Zhang et al ldquoBaicalin ameliorates H2O2

induced cytotoxicity in HK-2 cells through the inhibition of ERstress and the activation ofNrf2 signalingrdquo International Journalof Molecular Sciences vol 15 no 7 pp 12507ndash12522 2014

[80] H Ding H Wang Y Zhao D Sun and X Zhai ldquoProtectiveeffects of baicalin on A120573

1minus42minus induced learning and memory

deficit oxidative stress and apoptosis in ratrdquo Cellular andMolecular Neurobiology vol 35 no 5 pp 623ndash632 2015

[81] J C Silva H A Mariz L F Rocha Jr et al ldquoHydroxychloro-quine decreases Th17-related cytokines in systemic lupus ery-thematosus and rheumatoid arthritis patientsrdquo Clinics vol 68no 6 pp 766ndash771 2013

[82] D Park H Jeong M N Lee et al ldquoResveratrol inducesautophagy by directly inhibiting mTOR through ATP compe-titionrdquo Scientific Reports vol 6 Article ID 21772 2016

[83] A L Widlund J A Baur and O Vang ldquomTOR more targetsof resveratrolrdquo Expert Reviews in Molecular Medicine vol 15article e10 2013


[84] P-Y Tsai S-M Ka J-M Chang et al ldquoAntroquinonol differen-tially modulates T cell activity and reduces interleukin-18 pro-duction but enhances Nrf2 activation in murine acceleratedsevere lupus nephritisrdquo Arthritis and Rheumatism vol 64 no1 pp 232ndash242 2012

[85] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Together these data indicate that oxidative stress plays a keyrole in T cell dysfunction and the progression of lupus

2 Oxidative Stress and Treg Cells

Regulatory T (Treg) cells are capable of modulating thefunction of effector T cells maintaining immunologic home-ostasis and preventing autoimmunity [16] Circulating Tregnumbers decrease during disease flares in SLE patients andthe immune suppressive function of Treg cells in lupus isimpaired [17ndash21] The underlying reasons for this decreasein the number and function of Treg cells in SLE are notclear Foxp3 is essential for the development and functionof CD4+CD25+ regulatory T cells [22] and induction of thetranscription factor Foxp3 can transform CD4+CD25minus naıveT cells into CD4+CD25+ regulatory T cells [22] In additionTreg cell activity can be induced in the peripheral immunesystem by the conversion of naıve CD4+Foxp3minus T cells intoFoxp3+ T cells via transforming growth factor-beta (TGF-120573)[23 24] In addition interleukin- (IL-) 6 is a key cytokinethat inhibits Foxp3 expression during Treg cell differentiation[24] Previous studies have demonstrated that hyperoxia-induced stress and oxidative damage lead to an increase in IL-6 and concordantly increased production of IL-6 has beendocumented in SLE patients [24 25] Thus oxidative stress-induced increased production of IL-6 may be the primaryreason for the decrease in Treg cells in SLE patients

Activation of the mammalian target of rapamycin(mTOR) has recently emerged as a key sensor of MHP andmediator of enhancedCa2+ flux in lupusT cells [4 26]mTORis a ubiquitous serinethreonine kinase that is a criticalintegrator of environmental stimuli and regulates signalingin T cells to influence homeostasis differentiation andactivation [27 28] The effects of mTOR are cell type-specificand are elicited in response to stimulation by growth factorshormones and cytokines as well as in response to internaland external metabolic products [29] Recent observationshave demonstrated thatMHPand enhancedCa2+ fluxing inTcells contribute to injury in lupus [30 31] In T cells increasedproduction of nitric oxide and MHP were identified asmetabolic checkpoints upstream of mTOR activation [31 32]Additionally mTOR controls the expression of the TCR-associated signaling protein CD4 and through increasedexpression of the endosome recycling regulator HRES-1Rab4 mTORmediates enhanced Ca2+ flux skews the expres-sion of tyrosine kinases in T cells and blocks the expression ofFoxp3 and the expansion of regulatory cells [31 32]

Recently additional work further demonstrated thatmTOR controls the differentiation and functions of Treg cellssuggesting that its activity could be targeted to modulateTreg responses [27 29] Specifically mTOR was identifiedas a component of two interacting complexes mTORC1 andmTORC2 that regulate T cell lineage differentiation [33 34]Activation of mTOR delivers an obligatory signal for theproper activation and differentiation of effector CD4+ T cellswhereas in Treg cell differentiation the Akt-mTOR axis isa negative regulator of Treg cell [29 33 34] SpecificallymTORC1 drives the proinflammatory lymphocyte subset

expansion of T helper 1 (Th1) and T helper 17 (Th17) cellsmTORC2 favors the expansion of T follicular helper (Tfh)cells [35] which promote B cell activation and autoantibodyproduction [29] Both mTORC1 and mTORC2 inhibit thedevelopment of CD4+CD25+Foxp3+ Treg cells [29]

Furthermore mTORC1 activity is high in human andmurine Tregs [27 29 33 36] and this activity restrains TCRandor IL-2 stimulation-induced proliferation of Treg cells invitro [36] Rapamycin a lipophilic macrolide antibiotic thatregulates mitochondrial transmembrane potential and Ca2+flux has been used safely and effectively to treat lupus [31 3237] Rapamycin inhibitsmTORC1 in Tregs and then promotesTreg cell expansion in SLE patients [38] The effectiveness ofrapamycin in murine and human SLE further supports thenotion that mTOR is indeed a key mediator of autoimmunityin SLETherefore understanding themechanisms underlyingthe persistent MHP that leads to mTOR activation andenhanced Ca2+ flux is fundamental to understanding thepathogenesis of lupus [32]These findings suggest thatmTORblockade may increase life expectancy via treatment andprevention of SLE inflammatory injury [7 13 29]

Another T cell biology regulator is leptin which is ahormone derived from adipocytes Leptin is closely relatedto adipokines which are associated with oxidative stress andare reported to be overproduced in SLE patients [39 40]Previous data indicate that leptin signaling modulates T cellproliferation and preferential differentiation of Th1 cells overTh2 cells [41ndash43] Recently high levels of leptin receptorwere detected in Treg cells Interestingly leptin was foundto restrain Treg cell proliferation as neutralization of leptinenhanced TCR and IL-2-induced Treg cell expansion [43ndash45] Leptin receptor-deficient Treg cells also have increasedproliferative responses linked to reduced mTOR activation[36 41 46 47] Thus leptin sensing in Tregs is critical fordampening excessive mTOR activation and driving Treg pro-liferation [48] Both mTOR inhibition and amino acid depri-vation synergize with TGF-120573 to augment Foxp3 expression invitro [27 47 48] High leptin secretion has been reported inlupus patients and thus this secretion may be one of thekey reasons underlying the induction of mTORC1-meditatedinhibition of Treg cell differentiation as well as proinflamma-tory Th17 cell and other effector T cell expansion in SLE [2749 50] Recent study showed that superoxide production isincreased in all lymphocyte subsets of patients with antiphos-pholipid syndrome (APS) a special type of SLEThe oxidativestress was related to CD4+CD25+Foxp3+ Treg cell depletionin APS patients [51]

These data indicate that oxidative stress may contributeto the depletion of Treg cells in SLE patients suggesting thatantioxidation treatmentmay be an effectivemethod to relievelupus symptoms via improving Treg cell differentiationThusstrategies to enhance the number and function of Treg cellsmay benefit patients with SLE Leptin and mTOR may alsoserve as effective intervention targets to relieve oxidativestress and improve the differentiation of Treg cells in SLE(Figure 1) In addition Chinese herbs or compounds isolatedfrom natural herbs also appear to be promising therapeuticagents for control of the oxidative stress noted in SLE patients


FICZ uarr

AHR

Foxp3

Treg cells

mTORC1

TGF-120573IL-2

Rapamycin

Leptin uarr

IL-6 uarr










UV exposure uarr

FICZ uarr

H2O2 uarr

AHR

AHR

AHR

Hsp90

Hsp90 ARNT


Th17 cells

IL-17IL-21IL-22

Leptin uarr

TGF-120573IL-6

mTORC1uarr












Foxp3

mTORC1 mTORC2

STAT3

ROR120574t

Antioxidanttherapy

IL-17IL-21

TGF-120573IL-10



Th17

Th17

Normal stage

Oxidative stress

SLE patient

Healthy person







Disclosure


Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















FICZ uarr

AHR

Foxp3

Treg cells

mTORC1

TGF-120573IL-2

Rapamycin

Leptin uarr

IL-6 uarr










UV exposure uarr

FICZ uarr

H2O2 uarr

AHR

AHR

AHR

Hsp90

Hsp90 ARNT


Th17 cells

IL-17IL-21IL-22

Leptin uarr

TGF-120573IL-6

mTORC1uarr












Foxp3

mTORC1 mTORC2

STAT3

ROR120574t

Antioxidanttherapy

IL-17IL-21

TGF-120573IL-10



Th17

Th17

Normal stage

Oxidative stress

SLE patient

Healthy person







Disclosure


Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















UV exposure uarr

FICZ uarr

H2O2 uarr

AHR

AHR

AHR

Hsp90

Hsp90 ARNT


Th17 cells

IL-17IL-21IL-22

Leptin uarr

TGF-120573IL-6

mTORC1uarr












Foxp3

mTORC1 mTORC2

STAT3

ROR120574t

Antioxidanttherapy

IL-17IL-21

TGF-120573IL-10



Th17

Th17

Normal stage

Oxidative stress

SLE patient

Healthy person







Disclosure


Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Foxp3

mTORC1 mTORC2

STAT3

ROR120574t

Antioxidanttherapy

IL-17IL-21

TGF-120573IL-10



Th17

Th17

Normal stage

Oxidative stress

SLE patient

Healthy person







Disclosure


Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Disclosure


Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















oxidative stress and treg and th17 dysfunction in systemic lupus

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