Mitochondrial reactive oxygen species drive proinflammatory cytokine production.

2011·1.3 MB·English

by  Naik, Edwina

Minireview
Mitochondrial reactive oxygen species drive
proinflammatory cytokine production
Edwina Naik and Vishva M. Dixit
High levels of reactive oxygen species (ROS) are observed in chronic human inflammasome­dependent or inflam­
diseases such as neurodegeneration, Crohn’s disease, and cancer. In addition masome­independent roles for ROS.
to the presence of oxidative stress, these diseases are also characterized by Using cells from patients with
deregulated inflammatory responses, including but not limited to proinflam- TNFR1­associated periodic syndrome
matory cytokine production. New work exploring the mechanisms linking ROS (TRAPS), along with a relevant mouse
and inflammation find that ROS derived from mitochondria act as signal- model, Bulua et al. (2011) demonstrate
transducing molecules that provoke the up-regulation of inflammatory that mtROS influences the transcription
e cytokine subsets via distinct molecular pathways. of proinflammatory cytokines such as
n IL­6. In its most severe form, TRAPS
i
c The pleoitropic effect of inflammatory but also by influencing apoptosis, cell manifests as episodes of fever and severe
i
d cytokines demands complex and multi­ cycle, and metabolism. Mitochondria localized inflammation that is associated
e faceted regulation to limit collateral generate ATP through aerobic respira­ with “structural” mutations in TNFR1.
M
damage to normal tissue. On one level, tion, whereby glucose, pyruvate, and These TNFR1 mutations interfere with

l inflammatory cytokines such as inter­ NADH are oxidized, thus generating down­regulation of cell surface TNFR
a
t leukin 1 (IL­1) and IL­18 exist as in­ ROS as a byproduct. In normal cir­ expression, result in retention of the re­
n
e active zymogens that require proteolytic cumstances, the deleterious effects ceptor within the endoplasmic reticu­
m cleavage mediated by the inflammasome caused by the highly reactive nature of lum, confer ligand (TNF) independence,
i (Martinon et al., 2008). This proteolytic ROS are balanced by the presence of and prolong the cytokine response to
r
e maturation acts in concert with NF­B– antioxidants, including glutathione, lipopolysaccharide (LPS; McDermott
p
x dependent transcriptional activation of carotenoids, and antioxidant enzymes et al., 1999; Simon et al., 2010; Bulua
E genes encoding the zymogens to catalyze such as catalase and glutathione peroxi­ et al., 2011).

f a substantial increase in the levels of se­ dase. However, several chronic human Bulua et al. (2011) found higher
o
creted, bioactive protein. Other inflam­ diseases associated with inflammation baseline levels of mtROS in monocytes
l
a matory cytokines such as tumor necrosis are also characterized by excessive and neutrophils from TRAPS patients
n
factor (TNF) and IL­6 are induced pri­ ROS production (Drake et al., 1998; and in mouse embryonic fibroblasts
r
u marily at the transcriptional level and, in Cominelli, 2004; Reuter et al., 2010). (MEFs) engineered to express hetero­
o
the case of TNF, subject to posttranscrip­ Perhaps not surprisingly, defective mi­ zygous TRAPS­associated TNFR1 mu­
J
e tional messenger RNA stabilization by tochondria have also been implicated tations. The enhancement of ROS levels
h virtue of the dissociation of the mRNA­ in human diseases with underlying in­ in the mutant MEFs correlated with an
T
binding protein tristetraprolin from its flammatory pathologies, such as diabe­ increase in the levels of active JNK and
adenine­ and uridine­rich (ARE) region tes mellitus and cardiac dysfunction p38, a finding consistent with previous
(Anderson, 2000). Although these are (DiMauro and Schon, 2003; Nisoli et al., research linking persistent MAPK acti­
well­established mechanisms of regulat­ 2007; Patti and Corvera, 2010). vation to manifestation of the TRAPS
ing proinflammatory cytokine produc­ Three recent publications, includ­ phenotype (Simon et al., 2010). Inhibi­
tion, it is becoming apparent that an ing Bulua et al. in this issue, indicate tion of mtROS production inhibited
additional layer of complexity exists; i.e., that mitochondrial ROS (mtROS) MAPK activation and production of
signals provided by ROS. act as signaling molecules to trigger IL­6 and TNF in cells from TRAPS
The mitochondrion plays a critical proinflammatory cytokine production patients (Bulua et al., 2011), a finding
role in cell survival, most prominently (Nakahira et al., 2011; Zhou et al., consistent with a previous study showing
by generating the vast majority of a cell’s 2011). These observations provide that ROS can inactivate MAPK phos­
supply of adenosine triphosphate (ATP), much needed clarification about the phatases (Kamata et al., 2005). Thus,
cellular source of ROS that impacts mitochondria are the cellular source of
the production of certain inflammatory
E. Naik and V.M. Dixit are at Genentech, Inc., South
© 2011 Naik and Dixit This article is distributed under the terms of
San Francisco, CA 94080. cytokines. Although all three publica­ an Attribution–Noncommercial–Share Alike–No Mirror Sites license
tions underscore the importance of for the first six months after the publication date (see http://www
CORRESPONDENCE .rupress.org/terms). After six months it is available under a Creative
mtROS­dependent signaling, they dif­ Commons License (Attribution–Noncommercial–Share Alike 3.0
Vishva M. Dixit:
Unported license, as described at http://creativecommons.org/
[email protected] fer most notably by describing either licenses/by-nc-sa/3.0/).
The Rockefeller University Press $30.00
J. Exp. Med. Vol. 208 No. 3 417-420 417
www.jem.org/cgi/doi/10.1084/jem.20110367
the excessive ROS in TRAPS, and a Pharmacological interventions, such lacking NLRP3, caspase­1, or IL­1R
delicate equilibrium between MAP ki­ as IL­1 antagonists, which are used to produce normal levels of TNF and
nase and phosphatase activity defines a treat cryopyrinopathies caused by per­ IL­6 after LPS stimulation (Bulua et al.,
rheostat regulated primarily by the levels turbed inflammasome activation, have 2011). These observations confirm that
of mtROS, which in turn enables an limited efficacy for the treatment of neither mtROS production nor the
inflammatory response to proceed in a TRAPS. Although it is anticipated that signals transduced by mtROS depend
timely and effective fashion. Notably, mechanisms of reducing mtROS levels on activation of the inflammasome.
LPS­induced IL­6 production was re­ may be of therapeutic utility for TRAPS, In a critical mechanistic divergence,
duced even in healthy cells treated with it remains to be determined how two recent studies (Nakahira et al.,
mtROS inhibitors, indicating that this mtROS levels themselves are modu­ 2011; Zhou et al., 2011) identify an
signaling cascade is relevant to the induc­ lated. However, some insight is provided inflammasome­dependent role for
tion of a normal inflammatory response. by the observation that macrophages mtROS (Fig. 1).
Figure 1. Putative mechanisms of ROS-dependent proinflammatory cytokine production in normal, healthy cells. During inflammasome-
independent proinflammatory cytokine production (left), mtROS modulates the equilibrium between positive and negative regulators, which results in an
increase in the rate of transcription of cytokines such as IL-6. Several steps in this pathway require further investigation. Specifically, how does activation
of TLR4 by LPS result in an increase in ROS production from an individual mitochondrion (A), and how does mtROS inhibit negative regulators (e.g., MAPK
phosphatases) of cytokine gene transcription (B)? Inflammasome-dependent proinflammatory cytokine production (right) requires inhibition of autoph-
agy and mitophagy to increase the net amount of mtROS within the cell. The mechanism of this inhibition is unknown (C). Once mtROS accumulates, it
activates the NLRP3 inflammasome, but the mechanism of this activation remains undefined (D). Once activated, the NLRP3 inflammasome undergoes a
conformational change and assembles into a homooligomeric complex (one subunit is depicted) that catalyzes the activation of pro–caspase-1. In the
case of IL-, the active p10-p20 caspase-1 heterodimer cleaves pro–IL-1 to produce a mature form that is subsequently exported from the cell. AP-1,
activator protein 1; ASC, apoptosis-associated speck-like protein; CARD, caspase recruitment domain; DAMP, damage-associated molecular patterns; IRF,
interferon response factor; LRR, leucine-rich repeat; PAMP, pathogen-associated molecular patterns; PYD, pyrin domain.
418 ROS-dependent cytokine production | Naik and Dixit
Minireview
The inflammasome does not regu­ perturbation of basal levels of auto­ response? The cellular source of physio­
late transcription directly, but rather is phagy had a profound impact on the in­ logically relevant ROS is also stimulus
responsible for the activation of caspase­1, tegrity of the mitochondria, as Beclin dependent, as inflammatory signaling
an enzyme responsible for the proteo­ or LC3­deficient macrophages gener­ downstream of TLR ligation is depen­
lytic maturation of IL­1 and IL­18. ated more mitochondrial superoxide dent on mtROS, whereas crystalline
Since the initial identification of in­ anion radical (O ) in the absence of particles such as asbestos and silica re­
2
flammasomes, much interest has been stimulation. Thus, autophagy regulates quire both NADPH oxidase and mtROS
given to identifying the initiating events baseline mtROS production from indi­ (Dostert et al., 2008; Nakahira et al.,
that lead to the assembly of these multi­ vidual mitochondria by a yet to be 2011; Zhou et al., 2011). This under­
protein scaffolds. The multiplicity and identified mechanism. scores the importance of defining the
apparent divergent nature of NLRP3­ The release of mitochondrial physiologically relevant amount and
dependent stimuli have identified this DNA (mtDNA) in to the cytosol after source of ROS for each class of stimuli.
particular inflammasome as a focus of treatment of BMDMs with LPS and Further experiments will illuminate
investigation. Models posited for the ac­ ATP potentiated caspase­1 activation whether mtROS impacts other proin­
tivation of the NLRP3 inflammasome (Nakahira et al., 2011). Thus, mtDNA flammatory transcriptional networks,
include direct interaction with cognate is an additional secondary messenger even though it does not modulate IRF3­
ligand, and conformational alteration that acts as a surrogate marker of mito­ dependent induction of IFN­ (Bulua
induced by secondary messengers or chondrial dysfunction and also acti­ et al., 2011). Consequently, elucidating
alterations in the intracellular milieu vates caspase­1, presumably to amplify how ROS signaling acquires specificity
resulting from lysosomal rupture (Latz, the inflammatory response. This am­ for any given transcriptional network is
2010). Consistent with a secondary mes­ plification loop depends on NLRP3, of critical importance. Because of the
senger model, Zhou et al. (2011) and as NLRP3 deficiency suppressed the highly reactive nature of ROS, its signal
Nakahira et al. (2011) demonstrate that release of mtDNA after LPS and transduction properties are likely to in­
after an inflammatory stimulus, the ac­ ATP stimulation. clude direct chemical modification of its
cumulation of damaged mitochondria Collectively, these two investigations targets and/or catalysis of enzymatic
precipitates an increase in mtROS pro­ clearly established that in normal reactions (e.g., H O ). Indeed, the redox
2 2
duction, which in turn enhances in­ healthy cells the process of mitophagy regulator superoxide (SOD­1) modi­
flammasome activation. is a critical negative regulator of inflam­ fies the redox­sensitive cysteines of
Autophagy is the process of “self­ masome activation. This implies that ac­ caspase­1 to modulate its activation
digestion” that occurs by delivery of tive inhibition of autophagy is required (Meissner et al., 2008). NLRP3 and ASC
self­components to the lysosomal ma­ for proinflammatory signaling to pro­ relocalize to the mitochondria after in­
chinery. Mitophagy is a specialized ceed, for damaged mitochondria to ac­ flammasome activation (Zhou et al.,
form of autophagy that refers to the cumulate, for intracellular mtROS to 2011), but whether this relocalization
specific catabolism of mitochondria. increase, for mtDNA release, and for facilitates such modifications has yet
Pharmacological inhibition of auto­ the NLRP3 inflammasome to be acti­ to be demonstrated and is much antici­
phagy by treatment of macrophages vated. Consequently, a pressing ques­ pated. Another important issue is
with 3­methyladenine resulted in the tion is, how do NLRP3­dependent whether mtROS, or ROS in general,
accumulation of damaged mitochondria stimuli inhibit autophagy? influences the activation of other in­
and an increase in the net amount of The intimate relationship between flammasomes such as IPAF/NLRC4
mtROS (Zhou et al., 2011). IL­1 se­ mtROS production and proinflamma­ or AIM2 inflammasomes. The observa­
cretion induced by mtROS elevation tory cytokine activation is now well tion that macrophages lacking the
was abolished in Nlrp3/ and Asc/ established. The fact that different cyto­ IPAF/NLRC4 inflammasome respond
cells, thus confirming that the NLRP3 kines are subjected to distinct regula­ normally to artificial induction of ROS
inflammasome is activated in a ROS­ tory events, simplistically defined as and that mtROS production is dispens­
dependent manner. In bone marrow­ either transcriptional or posttranslational, able for activation of IPAF and AIM2
derived macrophages (BMDMs), genetic suggests that the generality of any given inflammasomes (Zhou et al., 2011) ar­
deletion of the autophagy­related pro­ mechanism is likely to be limited. The gues against this and raises the question
tein LC3B, which prevents the forma­ distinct temporal regulation of IL­1 of how specificity for the NLRP3­
tion and maturation of autophagosomes, (early response) and TNF and IL­6 (late inflammasome is acquired. Answers to
also enhanced caspase­1 activation and response) also suggests that different such challenging questions will provide
production of IL­1 and IL­18 in re­ cytokines will be influenced in distinct further refinement of the model of
sponse to the inflammasome­dependent ways by the production of mtROS. For ROS­dependent proinflammatory cyto­
stimuli LPS and ATP (Nakahira et al., example, are MAPK phosphatases only kine production, as well as information
2011). Similar results were observed after inhibited in the presence of higher necessary for the development of novel
deletion of the critical upstream regu­ levels of mtROS that presumably accu­ therapeutic interventions for ROS­
lator of autophagy, Beclin 1. In addition, mulate at later stages of an inflammatory driven human diseases.
JEM VOL. 208, March 14, 2011 419
REFERENCES Kamata, H., S. Honda, S. Maeda, L. Chang, H. mitochondrial DNA mediated by the NALP3
Hirata, and M. Karin. 2005. Reactive oxygen inflammasome. Nat. Immunol. 12:222–230.
Anderson, P. 2000. Post­transcriptional regulation
of tumour necrosis factor alpha production. species promote TNFalpha­induced death doi:10.1038/ni.1980
Ann. Rheum. Dis. 59:i3–i5. doi:10.1136/ and sustained JNK activation by inhibiting Nisoli, E., E. Clementi, M.O. Carruba, and S.
ard.59.suppl_1.i3 MAP kinase phosphatases. Cell. 120:649–661. Moncada. 2007. Defective mitochondrial bio­
Bulua, A.C., A. Simon, R. Maddipati, M. Pelletier, doi:10.1016/j.cell.2004.12.041 genesis: a hallmark of the high cardiovascular
H. Park, K.­Y. Kim, M.N. Sack, D.L. Kastner, Latz, E. 2010. The inflammasomes: mechanisms of risk in the metabolic syndrome? Circ. Res. 100:
and R.M. Siegel. 2011. Mitochondrial reac­ activation and function. Curr. Opin. Immunol. 795–806. doi:10.1161/01.RES.0000259591
tive oxygen species promote production of 22:28–33. doi:10.1016/j.coi.2009.12.004 .97107.6c
proinflammatory cytokines and are elevated Martinon, F., A. Major, and J. Tschopp. 2008. The Patti, M.­E., and S. Corvera. 2010. The role of
in TNFR1­associated periodic syndrome inflammasomes: guardians of the body. Annu. mitochondria in the pathogenesis of type 2 di­
(TRAPS). J. Exp. Med. 208:519–533. Rev. Immunol. 27:229–265. doi:10.1146/ abetes. Endocr. Rev. 31:364–395. doi:10.1210/
Cominelli, F. 2004. Cytokine­based therapies for annurev.immunol.021908.132715 er.2009­0027
Crohn’s disease—new paradigms. N. Engl. J. Med. McDermott, M.F., I. Aksentijevich, J. Galon, Reuter, S., S.C. Gupta, M.M. Chaturvedi, and B.B.
351:2045–2048. doi:10.1056/NEJMp048253 E.M. McDermott, B.W. Ogunkolade, M. Aggarwal. 2010. Oxidative stress, inflamma­
DiMauro, S., and E.A. Schon. 2003. Mitochondrial Centola, E. Mansfield, M. Gadina, L. Karenko, tion, and cancer: how are they linked? Free
respiratory­chain diseases. N. Engl. J. Med. T. Pettersson, et al. 1999. Germline muta­ Radic. Biol. Med. 49:1603–1616. doi:10.1016/
348:2656–2668. doi:10.1056/NEJMra022567 tions in the extracellular domains of the 55 j.freeradbiomed.2010.09.006
Dostert, C., V. Pétrilli, R. Van Bruggen, C. kDa TNF receptor, TNFR1, define a fam­ Simon, A., H. Park, R. Maddipati, A.A. Lobito,
Steele, B.T. Mossman, and J. Tschopp. 2008. ily of dominantly inherited autoinflamma­ A.C. Bulua, A.J. Jackson, J.J. Chae, R.
Innate immune activation through Nalp3 tory syndromes. Cell. 97:133–144. doi:10 Ettinger, H.D. de Koning, A.C. Cruz, D.L.
inflammasome sensing of asbestos and .1016/S0092­8674(00)80721­7 Kastner, H. Komarow, and R.M. Siegel.
silica. Science. 320:674–677. doi:10.1126/ Meissner, F., K. Molawi, and A. Zychlinsky. 2008. 2010. Concerted action of wild­type and
science.1156995 Superoxide dismutase 1 regulates caspase­1 mutant TNF receptors enhances inflam­
Drake, I.M., N.P. Mapstone, C.J. Schorah, K.L.M. and endotoxic shock. Nat. Immunol. 9:866– mation in TNF receptor 1­associated peri­
White, D.M. Chalmers, M.F. Dixon, and 872. doi:10.1038/ni.1633 odic fever syndrome. Proc. Natl. Acad. Sci.
A.T.R. Axon. 1998. Reactive oxygen species Nakahira, K., J.A. Haspel, V.A.K. Rathinam, S.­J. USA. 107:9801–9806. doi:10.1073/pnas
activity and lipid peroxidation in Helicobacter Lee, T. Dolinay, H.C. Lam, J.A. Englert, M. .0914118107
pylori associated gastritis: relation to gastric Rabinovitch, M. Cernadas, H.P. Kim, K.A. Zhou, R., A.S. Yazdi, P. Menu, and J. Tschopp.
mucosal ascorbic acid concentrations and ef­ Fitzgerald, S.W. Ryter, and A.M. Choi. 2011. A role for mitochondria in NLRP3 in­
fect of H pylori eradication. Gut. 42:768–771. 2011. Autophagy proteins regulate innate flammasome activation. Nature. 469:221–225.
doi:10.1136/gut.42.6.768 immune responses by inhibiting the release of doi:10.1038/nature09663
420 ROS-dependent cytokine production | Naik and Dixit