Journal of Inflammation Research

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The role of inflammation and interleukin-1

in acute cerebrovascular disease
This article was published in the following Dove Press journal:
Journal of Inflammation Research
19 August 2013
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James Galea 1
David Brough 2
Manchester Academic Health
Sciences Center, Brain Injury
Research Group, Clinical Sciences
Building, Salford Royal Foundation
Trust, Salford, UK; 2Faculty of Life
Sciences, University of Manchester,
AV Hill Building, Manchester, UK
1

Abstract: Acute cerebrovascular disease can affect people at all stages of life, from neonates
to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute
cerebrovascular disease is multifactorial with many mechanisms contributing to a complex
pathophysiology. One of the major processes worsening disease severity and outcome is
inflammation. Pro-inflammatory cytokines of the interleukin (IL)-1 family are now known to
drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent
literature describing the role of IL-1in acute cerebrovascular disease and to provide an update
on our current understanding of the mechanisms of IL-1 production. We also discuss the recent
literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential
future strategies that may limit the devastating effects of acute cerebrovascular disease.
Keywords: cerebral ischemia, stroke, inflammation, microglia, interleukin-1, caspase-1

Acute cerebrovascular disease

Correspondence: David Brough

Faculty of Life Sciences, University of
Manchester, AV Hill Building, Oxford
Road, Manchester, M13 9PT, UK
Tel +44 161 275 5039
Fax +44 161 275 5948
Email david.brough@manchester.ac.uk

Acute cerebrovascular disease is a myriad of clinical conditions that can present in

many different ways, from periventricular hemorrhage in preterm babies, through
subarachnoid hemorrhage (SAH), ischemic and hemorrhagic stroke, and vascular
dementia in middle and old age.
Evidence based treatments for acute stroke are limited to thrombolysis for up to
20% of all strokes, antiplatelet agents, and stroke unit care. There is some evidence
for decompressive craniectomy in highly selected patients as a life saving measure,
and ongoing trials are investigating the efficacy of endovascular interventions such
as thrombectomy for acute ischemic stroke. For SAH, there is currently no treatment
that addresses the ischemic injury occurring at ictus and the use of nimodipine still
results in up to a third of patients developing delayed cerebral ischemia. In intracerebral
hemorrhage (ICH), no current therapies other than those addressing hypertension at
presentation improve the outcome,1 and surgical trials including the recent Surgical
Trial in Lobar Intracerebral Haemorrhage (STICH II) study have also failed to show
any benefit.2 It is therefore evident that treatment of acute cerebrovascular disease
remains an area of unmet clinical need. While there have been numerous rodent
studies targeting inflammation, particularly in stroke, only a few of these have successfully translated into clinical practice. Furthermore, there remains a paucity of
research into the targeting of key molecular pathological mechanisms that underpin
neurodegeneration occurring in all of these processes. The purpose of this review is
to discuss the potential for targeting a pro-inflammatory cytokine called interleukin
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2013 Galea and Brough. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution Non Commercial (unported,v3.0)
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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http://dx.doi.org/10.2147/JIR.S35629

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Galea and Brough

(IL)-1 and its regulatory processes as potential treatments

for cerebrovascular disease.

Inflammation
Inflammation is an important host defense response to
injury or infection. Key to an inflammatory response is the
recruitment of polymorphonuclear cells to the site of injury
or infection. This response is coordinated by cascades of
cellular and molecular events that include the production of
pro-inflammatory mediators such as cytokines, chemokines,
and cell adhesion molecules. Many of the tools of the inflammatory response that target pathogens, such as proteases
and reactive oxygen species, also kill healthy cells. This
collateral damage may be acceptable when compared to the
consequences of pathogen survival. However, when these
responses occur in the absence of infection, during injury, or
noncommunicable disease states, this collateral damage leads
to a worsening of the condition and as such represents a therapeutic target.3 Inflammation in the context of injury, and in
the absence of infection, is considered as sterile inflammation.
Acute brain cerebrovascular disease results primarily from a
disruption to blood flow to a region of the brain and thus the
inflammation stimulated by such injuries can be considered
sterile. Cytokines of the IL-1 family, namely the IL-1 and
IL-1 isoforms, are strongly implicated in sterile inflammatory responses that worsen acute cerebrovascular disease.4

IL-1 production
In a healthy brain, IL-1 is undetectable, but it is expressed
after an injury or during disease.5 For example, in an animal
model of stroke (induced by occlusion of the middle cerebral
artery), a rapid increase in expression of both IL-1,6 and
IL-1 are observed in microglia within hours of the insult
and within areas of the brain that experience cell death.7
Although IL-1 and IL-1 appear to be produced mainly
by microglia in this model, there is evidence that astrocytes
may also express IL-1.7,8 Microglia expressing IL-1 are also
observed in regions adjacent to the bleed site in a rat model
of SAH.9 Preclinical pharmacological or genetic manipulation studies have demonstrated a consistently detrimental
effect of IL-1in experimental stroke.10 In clinical studies,
increased intrathecal concentrations of IL-1 are associated with increased injury,11 and with increased incidence
of vasospasm following SAH.12 IL-1induces release of the
inflammatory mediator IL-6 from glia and neurons through
type-1 receptor IL-1RI signaling.13,14 IL-6 concentrations
are more readily detectable and tend to be more consistent
over time. IL-6 is increased in cerebrovascular disease within

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the cerebrospinal fluid (CSF) and the brain extracellular fluid.

In stroke, intrathecal IL-6 concentrations correlate with lesion
size,11,15 while in SAH, increased intrathecal IL-6 concentrations are associated with demonstrable vasospasm.12
IL-1 expression is stimulated by molecular motifs
expressed by pathogens termed pathogen associated molecular patterns, or by molecules released from dead or injured
tissue/cells, or that are modified during disease called damage associated molecular patterns (DAMPs). DAMPs are
endogenous molecules normally retained within cells and
thus not exposed to immune surveillance. Upon their release
during cell death, DAMPs are sensed by pattern recognition
receptors (PRRs) on the membranes of cells of the innate
immune system, such as microglia, resulting in signaling
cascades that induce the expression of pro-inflammatory
cytokines.16,17 The specific DAMPs that drive the expression
of IL-1 after an acute brain injury are unknown, although
there are many potential candidates identified from other
disease states including high mobility group protein B1, heat
shock proteins, heparin sulfate, and many other endogenous
molecules released by dying cells.17 Acute phase proteins
such as serum amyloid A may also induce expression of
IL-1in microglia after a brain injury after gaining access to
the brain through a damaged bloodbrain barrier.18 Many
of the DAMPs discovered stimulate PRRs of the toll-like
receptor (TLR) family, resulting in the activation of signaling
pathways such as nuclear factor-B and p38mitogen activated protein kinase that regulate the expression of multiple
inflammatory genes in addition to IL1A and IL1B.19 TLRs
share a conserved toll- and IL-1 receptor related domain
with IL-1RI, and thus TLRs and IL-1RI share many common
signaling steps following stimulation.19,20
Many pro-inflammatory mediators have conventional
secretory routes from the cell, but perhaps indicative of their
position as master cytokines, IL-1 and IL-1 are subject
to an additional regulatory step. Stimulating cells to express
IL-1 is often referred to as a priming step. A second stimulus
is required to elicit their cellular release.21 Both IL-1 forms are
initially produced as precursors that reside in the cytoplasm
of the cell following the initial priming step. Pro-IL-1 is
inactive at IL-1RI, and requires proteolytic cleavage to yield
a mature, secreted, biologically active molecule. Pro-IL-1
has some biological activity, which is strongly enhanced
following proteolytic cleavage (Figure1).22,23

IL-1 processing and secretion

The protease most commonly reported to cleave pro-IL-1
is caspase-1. Caspase-1 is also produced as an inactive

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Inflammation and brain injury

DAMPs

ac
l surf
l
e
C

e DAMP receptor signa

lli

ng

Inflammasome

NF-B

Pro-IL-1
Pro-IL-1
Surface IL-1

Mature IL-1

IL-1

Cell surface IL-1RI

Figure1 The development of inflammation in acute cerebrovascular disease.

Notes: Cell death as a result of acute cerebrovascular disease results in the generation of numerous damage associated molecular patterns (DAMPs) that act on pattern
recognition receptors on immune cells to initiate and shape the inflammatory response. DAMPs stimulate priming, resulting in increased expression of interleukin (IL)-1,
and also stimulate inflammasome assembly, activation of caspase-1, and of other proteases capable of processing and activating IL-1. IL-1 (both IL-1 and IL-1) is released
and can then stimulate the type I IL-1 receptor on responsive cells to trigger inflammatory signaling pathways with pleiotropic effects.
Abbreviations: DAMPs, damage associated molecular patterns; NF-B, nuclear factor-B; IL, interleukin; IL-1R1, type I IL-1 receptor.

precursor however, and a primed cell must encounter a

secondary stimulus that facilitates the activation of caspase-1.
The secondary stimulus that drives IL-1 processing and
release during sterile disease is an additional DAMP. During sterile inflammation the secondary stimulus is typically
sensed by a cytosolic PRR called NACHT, LRR and PYD
domains-containing protein (NLRP) 3.24 Sterile activators
of NLRP3include (but not exclusively) molecules such as
adenosine triphosphate (ATP),25 sphingosine,26 and monosodium urate.27 There is limited evidence supporting a direct
interaction between DAMP and NLRP3 and additional host
cellular signals such as K+ efflux,28 lysosomal destabilization and cathepsin activity,29 and ROS production and/or
mitochondrial dysfunction,30 are suggested to be important.

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Once activated NLRP3interacts via an interaction of pyrin

domains with an adaptor protein called apoptosis-associated
speck-like protein containing a caspase recruitment domain
(ASC). ASC recruits pro-caspase-1 into the complex via
an interaction of caspase activation and recruitment domain
(CARD) that subsequently results in caspase-1 activation
and processing of pro-IL-1. This multimolecular IL-1
processing complex is called the inflammasome.31 A role for
the NLRP3inflammasome in brain inflammation has been
suggested using animal models of Alzheimers disease and
multiple sclerosis.32,33 However, there is as yet no evidence
to support a role of NLRP3in ischemic brain injury. Another
inflammasome forming PRR that is found in the brain is
NLRP1,34 which is expressed by neurons.35 NLRP1 has

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a CARD and can thus interact with caspase-1 directly,36

although the presence of ASC does appear to enhance its
activity.37 The NLRP1 inflammasome is suggested to be
important in rodent models of acute CNS injury through
studies using neutralizing antibodies in models of spinal
cord injury and traumatic brain injury in the rat,38,39 and in a
mouse model of thromboembolic stroke.40
Once processed, IL-1 is secreted rapidly from the
cell into the extracellular environment where it stimulates
signaling pathways on IL-1RI expressing cells. The precise
mechanisms of IL-1 secretion are poorly understood. IL-1
does not follow the conventional endoplasmic reticulumgolgi pathway of secretion and harnesses one or more of
the nonconventional secretory routes. We have recently
reviewed the literature for mechanisms of IL-1 secretion
and postulated that the mechanism involved may depend on
the strength of the inflammatory stimulus.21 Based on this
simple theory we classified IL-1 secretion mechanisms as
(1) rescue and redirect where IL-1 targeted for degradation
via lysosomal or autophagic routes could be rescued and
secreted; (2) protected release where IL-1 is contained
in secreted vesicles such as microvesicles shed from the
plasma membrane, or exosomes released by the exocytosis
of multivesicular bodies; and (3) terminal release where
IL-1 is secreted through pores in the plasma membrane,
with these pores ultimately resulting in an osmotic lysis of
the cell. Whilst the vast majority of the literature reporting
IL-1 release focuses on the inflammasome, it is important
to note that additional caspase-1independent mechanisms
exist, and of particular relevance to sterile disease may be
extracellular processing of pro-IL-1 by neutrophil derived
proteases including proteinase 3.41,42 An extracellular
cathepsin D dependent processing of pro-IL-1 has also
been reported to occur from microglia stimulated with ATP
under acidic conditions.43
In contrast to IL-1, there has been comparatively little
research into the mechanisms of IL-1 processing and
secretion. The secretion of IL-1 in response to DAMP stimulation is also reported to depend upon the inflammasome.44
Pro-IL-1 is not a substrate for caspase-1 and it is not clear
how inflammasome activation regulates its processing and
release, although a non-catalytic role of caspase-1 and calpain
protease dependent processing are implicated.44,45 An alternative23 to this model was proposed recently where pro-IL-1
binds tightly to an intracellular form of the type II IL-1 receptor (IL-1RII). Upon activation of the inflammasome, IL-1RII
is cleaved by caspase-1 rendering pro-IL-1 available for

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calpain mediated cleavage.23 Granzyme B is also reported

to cleave pro-IL-1 leading to an increase in its biological
activity.22 In contrast to IL-1, pro-IL-1 can traffic to the
nucleus of the expressing cell and this mechanism may limit
IL-1 release during cell death.46

Consequences of IL-1 signaling

IL-1 released by microglia into the extracellular space can act
directly on nearby neurons. IL-1 stimulates the activation of
Src tyrosine kinases in neurons which results in phosphorylation of the NR2A and NR2B N-methyl-D-aspartate (NMDA)
receptor subunits.47 This subsequently results in increased
calcium flux after NMDA receptor activation and increased
excitotoxic cell death.47 IL-1 can also exert neurotoxic
effects via glial cell dependent production of reactive oxygen
and proteases.48,49 In a microglia-neuron coculture model,
aggregated amyloid- (pathological feature of Alzheimers
disease) induced neurotoxicity was lost when caspase-1
knockout microglia were used instead of wildtype.50 Thus,
local effects of IL-1 dependent signaling could contribute
to brain injury.
We now know that in addition to centrally produced
IL-1, peripheral sources also contribute to brain inflammation after experimental stroke.51 Systemic IL-1 exacerbates
neuronal injury after experimental stroke by increasing the
production and infiltration of neutrophils into the ischemic
tissue.52 This neutrophil dependent toxicity is at least in part
dependent upon a matrix metalloproteinase induced disruption of the bloodbrain barrier.53 In a culture system, platelet
derived IL-1 can activate brain endothelial cells to produce
chemokines and increase expression of adhesion molecules,
thus facilitating the transmigration of neutrophils across an
endothelial cell layer.54 Transmigrated neutrophils were
recently shown to be neurotoxic via a mechanism dependent upon proteases associated with neutrophil extracellular
traps.55 Thus, multiple sources and effects of IL-1may contribute to the inflammation dependent damage that occurs
during acute cerebrovascular disease.
Another consequence of IL-1 dependent inflammation
in acute cerebrovascular disease is immune depression,
which contributes to a susceptibility to infection.56,57 This is
of particular clinical relevance, where infections following
ischemic stroke58,59 and SAH60 are observed with increased
frequency, and are a major cause of morbidity in those
surviving the initial insult. This phase of immune depression represents an unbalanced peripheral anti-inflammatory
reaction following the initial insult,56,61 and results in altered

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lymphocyte function62 and depletion,63 reduced natural

killer cell function,64 and a shift from Th1 to Th2 cytokine
response.65 The two main mechanisms that are thought to
cause immune depression after an acute brain injury are
(1) stimulation of the hypothalamic-pituitary-adrenal axis
releasing adrenal cortisol, and (2) catecholamine mediated
IL-10 release.57,66 IL-1 and IL-6 are direct inducers of both
mechanisms.56,67 Our research group has also demonstrated
the central role of IL-1in poststroke immune depression by
inducing its reversal with the IL-1 receptor antagonist (IL-1Ra).68 Further studies are currently underway in SAH and
ICH. In ICH, although a reduction in white blood cells is
not usually observed,69 there is clinical evidence that plasma
IL-10 concentrations are raised which may contribute to
immune depression and increased risk of infection.70

Targeting inflammation in acute

cerebrovascular disease
A variety of pharmacological interventions against the
IL-1system have been studied in experimental models of
acute cerebrovascular disease where they have been shown
to limit neuronal injury.71 We have recently reviewed these
in more depth elsewhere,71 but briefly, they range from biologicals such as IL-1Ra and neutralizing IL-1 antibodies,
to small molecule inhibitors of inflammatory signaling pathways and caspase-1.71 Although protective effects observed
when targeting nuclear factor-B or p38mitogen activated
protein kinase could be ascribed to a plethora of inflammatory signaling processes, at least comparable neuroprotective
effects are observed with agents that specifically target the
IL-1 pathway. Caspase-1 inhibitors are highly protective
in rodent models of acute cerebrovascular disease. 7274
Antibodies that target IL-1 directly,75 or components of the
NLRP1inflammasome are also protective in experimental
models.39,40 For many years, IL-1Ra has been known to offer
significant neuroprotection in experimental models of brain
injury.5 These studies have recently been extended to animals
with comorbidities commonly seen in stroke patients, where
similar neuroprotective effects of IL-1Ra are also reported.76
Clinically, IL-1Ra has also been administered to patients with
ischemic and hemorrhagic stroke where it was effective in
reducing peripheral markers of inflammation.77 In patients
with SAH, IL-1Ra has been administered through both
intravenous78 and subcutaneous routes (Galea, unpublished
data, 2012). Intravenous IL-1Ra has been demonstrated to
penetrate CSF and achieve concentrations that are associated
with neuroprotection in rodent studies.79 Together these data

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Inflammation and brain injury

suggest that targeting the IL-1system could represent a real

opportunity for treating acute cerebrovascular disease.

Conclusions, open questions,

and future perspectives
In summary, there is compelling evidence to suggest that
effective targeting of the IL-1system could be therapeutic
in the treatment of acute cerebrovascular disease. Despite the
large number of potential DAMPs and signaling pathways
involved in the regulation of IL-1, its actions depend entirely
on IL-1RI activation, which is the only known signaling
receptor for IL-1 and IL-1 (Figure 1). Perhaps that is
why IL-1Ra has proven to be so effective and is showing
the greatest promise currently. Importantly IL-1Ra is also
protective in comorbid models of stroke in rodents which
better reflect the human condition.76
In addition to nonrepresentative animal models, there are
other reasons for the persistent failure of drugs that require
an appreciation of the underlying biological pathways.
Changes in the activity of single enzymes normally have
only small effects on pathway fluxes, and multisite modulation is necessary to effect large changes in fluxes.80 Targeting multiple nodes in a signaling network may therefore
be a more effective therapeutic strategy.81 The potential of
this approach has already been demonstrated in a number
of cellular models, including our own work on the expression of IL-1.82 The existence of such dynamic interactions
and changes within the inflammatory cascade may thus be
overcome by approaches that target multiple points within
the inflammatory cascade.
At the fundamental level there exist a number of
questions. Many arise from our yet incomplete understanding of inflammasome priming and activation and assembly,
and the mechanism of secretion for IL-1. More specifically,
the mechanisms and inflammasomes regulating IL-1in acute
brain injury remain unknown. Relative contributions of IL-1
and IL-1 to the expanding infarct or developing ischemia
are also unknown. Understanding these processes will likely
lead to the identification of new therapeutic targets that may
further direct strategies to target the inflammation that occurs
during acute cerebrovascular disease.

Acknowledgments
We are grateful to Professors Nancy Rothwell and Pippa
Tyrrell, and to Dr Emmanuel Pinteaux (all from the University of Manchester), for providing detailed feedback on
a draft version of this manuscript.

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Disclosure
The authors report no conflicts of interest in this work.

References

1. Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of

injury and therapeutic targets. Lancet Neurol. 2012;11:720731.
2. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A,
Mitchell PM; for the STICH II Investigators. Early surgery versus initial
conservative treatment in patients with spontaneous supratentorial lobar
intracerebral haematomas (STICH II): a randomised trial. Lancet. Epub
May 29, 2013.
3. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory
response. Annu Rev Immunol. 2010;28:321342.
4. Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS
injury and disease. Br J Pharmacol. 2006;147(Suppl 1):S232S240.
5. Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury.
Nat Rev Immunol. 2005;5:629640.
6. Luheshi NM, Kovacs KJ, Lopez-Castejon G, Brough D, Denes A.
Interleukin-1alpha expression precedes IL-1beta after ischemic brain
injury and is localised to areas of focal neuronal loss and penumbral
tissues. J Neuroinflammation. 2011;8:186.
7. Amantea D, Bagetta G, Tassorelli C, Mercuri NB, Corasaniti MT.
Identification of distinct cellular pools of interleukin-1beta during the evolution of the neuroinflammatory response induced by transient middle cerebral artery occlusion in the brain of rat. Brain Res. 2010;1313:259269.
8. Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ. Role of CX3CR1
(fractalkine receptor) in brain damage and inflammation induced by
focal cerebral ischemia in mouse. J Cereb Blood Flow Metab. 2008;28:
17071721.
9. Greenhalgh AD, Brough D, Robinson EM, Girard S, Rothwell NJ,
Allan SM. Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory
pathology. Dis Model Mech. 2012;5:823833.
10. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in
experimental and human stroke. J Cereb Blood Flow Metab. 2012;32:
16771698.
11. Tarkowski E, Rosengren L, Blomstrand C, et al. Early intrathecal
production of interleukin-6 predicts the size of brain lesion in stroke.
Stroke. 1995;26:13931398.
12. Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels
in CSF in patients with vasospasm following aneurysmal SAH. Neuro
Endocrinol Lett. 2004;25:141147.
13. Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW. Cytokine
production by human fetal microglia and astrocytes. Differential
induction by lipopolysaccharide and IL-1 beta. J Immunol. 1993;150:
26592667.
14. Ringheim GE, Burgher KL, Heroux JA. Interleukin-6mRNA expression by cortical neurons in culture: evidence for neuronal sources
of interleukin-6 production in the brain. J Neuroimmunol. 1995;63:
113123.
15. Tarkowski E, Rosengren L, Blomstrand C, etal. Intrathecal release of
pro- and anti-inflammatory cytokines during stroke. Clin Exp Immunol.
1997;110:492499.
16. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to
damage. Nat Rev Immunol. 2010;10:826837.
17. Piccinini AM, Midwood KS. DAMPening inflammation by modulating
TLR signalling. Mediators Inflamm. 2010; Article ID 672395.
18. Savage CD, Lopez-Castejon G, Denes A, Brough D. NLRP3inflammasome activating DAMPs stimulate an inflammatory response
in glia in the absence of priming which contributes to brain inflammation
after injury. Front Immunol. 2012;3:288.
19. Newton K, Dixit VM. Signaling in innate immunity and inflammation.
Cold Spring Harb Perspect Biol. 2012;4:119.
20. Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal.
2010;19;3(105):cm1.

126

submit your manuscript | www.dovepress.com

Dovepress

Dovepress
21. Lopez-Castejon G, Brough D. Understanding the mechanism of IL-1beta
secretion. Cytokine Growth Factor Rev. 2011;22:189195.
22. Afonina IS, Tynan GA, Logue SE, et al. Granzyme B-dependent
proteolysis acts as a switch to enhance the proinflammatory activity of
IL-1alpha. Mol Cell. 2011;44:265278.
23. Zheng Y, Humphry M, Maguire JJ, Bennett MR, Clarke MC.
Intracellular interleukin-1 receptor 2 binding prevents cleavage and
activity of interleukin-1alpha, controlling necrosis-induced sterile
inflammation. Immunity. 2013;38:285295.
24. Cassel SL, Sutterwala FS. Sterile inflammatory responses mediated by
the NLRP3inflammasome. Eur J Immunol. 2010;40:607611.
25. Mariathasan S, Weiss DS, Newton K, et al. Cryopyrin activates the
inflammasome in response to toxins and ATP. Nature. 2006;440:
228232.
26. Luheshi NM, Giles JA, Lopez-Castejon G, Brough D. Sphingosine
regulates the NLRP3-inflammasome and IL-1beta release from
macrophages. Eur J Immunol. 2012;42:716725.
27. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated
uric acid crystals activate the NALP3inflammasome. Nature. 2006;
440:237241.
28. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J.
Activation of the NALP3 inflammasome is triggered by low
intracellular potassium concentration. Cell Death Differ. 2007;14:
15831589.
29. Hornung V, Latz E. Critical functions of priming and lysosomal damage
for NLRP3 activation. Eur J Immunol. 2010;40:620623.
30. Shimada K, Crother TR, Karlin J, etal. Oxidized mitochondrial DNA
activates the NLRP3 inflammasome during apoptosis. Immunity.
2012;36:401414.
31. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health
and disease. Nature. 2012;481:278286.
32. Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in
Alzheimers disease and contributes to pathology in APP/PS1 mice.
Nature. 2013;493:674678.
33. Jha S, Srivastava SY, Brickey WJ, et al. The inflammasome sensor,
NLRP3, regulates CNS inflammation and demyelination via caspase-1
and interleukin-18. J Neurosci. 2010;30:1581115820.
34. Yin Y, Yan Y, Jiang X, etal. Inflammasomes are differentially expressed
in cardiovascular and other tissues. Int J Immunopathol Pharmacol.
2009;22:311322.
35. Kummer JA, Broekhuizen R, Everett H, et al. Inflammasome components NALP 1 and 3show distinct but separate expression profiles
in human tissues suggesting a site-specific role in the inflammatory
response. J Histochem Cytochem. 2007;55:443452.
36. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821832.
37. Faustin B, Lartigue L, Bruey JM, etal. Reconstituted NALP1inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell.
2007;25:713724.
38. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW.
A molecular platform in neurons regulates inflammation after spinal
cord injury. J Neurosci. 2008;28:34043414.
39. de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM,
Dietrich WD, Keane RW. Therapeutic neutralization of the
NLRP1 inflammasome reduces the innate immune response and
improves histopathology after traumatic brain injury. J Cereb Blood
Flow Metab. 2009;29:12511261.
40. Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW,
Dietrich WD. Inhibition of the inflammasome complex reduces the
inflammatory response after thromboembolic stroke in mice. J Cereb
Blood Flow Metab. 2009;29:534544.
41. Fantuzzi G, Ku G, Harding MW, etal. Response to local inflammation
of IL-1 beta-converting enzyme-deficient mice. J Immunol. 1997;158:
18181824.
42. Joosten LA, Netea MG, Fantuzzi G, et al. Inflammatory arthritis in
caspase 1gene-deficient mice: contribution of proteinase 3 to caspase
1-independent production of bioactive interleukin-1beta. Arthritis
Rheum. 2009;60:36513662.

Journal of Inflammation Research 2013:6

Dovepress
43. Takenouchi T, Iwamaru Y, Sugama S, et al. The activation of P2X7
receptor induces cathepsin D-dependent production of a 20-kDa form
of IL-1beta under acidic extracellular pH in LPS-primed microglial
cells. J Neurochem. 2011;117:712723.
44. Gross O, Yazdi AS, Thomas CJ, etal. Inflammasome activators induce
interleukin-1alpha secretion via distinct pathways with differential
requirement for the protease function of caspase-1. Immunity. 2012;36:
388400.
45. Luheshi NM, Rothwell NJ, Brough D. Dual functionality of
interleukin-1 family cytokines: implications for anti-interleukin-1
therapy. Br J Pharmacol. 2009;157:13181329.
46. Luheshi NM, McColl BW, Brough D. Nuclear retention of IL-1 alpha
by necrotic cells: a mechanism to dampen sterile inflammation. Eur J
Immunol. 2009;39:29732980.
47. Viviani B, Bartesaghi S, Gardoni F, etal. Interleukin-1beta enhances
NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003;23:86928700.
48. Thornton P, Pinteaux E, Gibson RM, Allan SM, Rothwell NJ.
Interleukin-1-induced neurotoxicity is mediated by glia and requires
caspase activation and free radical release. J Neurochem. 2006;98:
258266.
49. Thornton P, Pinteaux E, Allan SM, Rothwell NJ. Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1induced neurotoxicity. Mol Cell Neurosci. 2008;37:135142.
50. Halle A, Hornung V, Petzold GC, etal. The NALP3inflammasome is
involved in the innate immune response to amyloid-beta. Nat Immunol.
2008;9:857865.
51. Denes A, Wilkinson F, Bigger B, Chu M, Rothwell NJ, Allan SM.
Central and haematopoietic interleukin-1 both contribute to ischaemic
brain injury in mice. Dis Model Mech. 2013;6:10431048.
52. McColl BW, Rothwell NJ, Allan SM. Systemic inflammatory
stimulus potentiates the acute phase and CXC chemokine responses to
experimental stroke and exacerbates brain damage via interleukin-1and neutrophil-dependent mechanisms. J Neurosci. 2007;27:
44034412.
53. McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the
kinetics of cerebrovascular tight junction disruption after experimental
stroke in mice. J Neurosci. 2008;28:94519462.
54. Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM,
Rothwell NJ. Platelet interleukin-1{alpha} drives cerebrovascular
inflammation. Blood. 2010;115:36323639.
55. Allen C, Thornton P, Denes A, et al. Neutrophil cerebrovascular
transmigration triggers rapid neurotoxicity through release of proteases
associated with decondensed DNA. J Immunol. 2012;189:381392.
56. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous
system injury-induced immune deficiency syndrome. Nat Rev Neurosci.
2005;6:775786.
57. Woiciechowsky C, Schoning B, Lanksch WR, Volk HD, Docke WD.
Mechanisms of brain-mediated systemic anti-inflammatory syndrome
causing immunodepression. J Mol Med (Berl). 1999;77:769780.
58. Weimar C, Roth MP, Zillessen G, etal. Complications following acute
ischemic stroke. Eur Neurol. 2002;48:133140.
59. Grabska K, Gromadzka G, Czlonkowska A. Infections and ischemic
stroke outcome. Neurol Res Int. 2011;2011:691348.
60. Stevens RD, Nyquist PA. The systemic implications of aneurysmal
subarachnoid hemorrhage. J Neurol Sci. 2007;261:143156.
61. Iadecola C, Anrather J. The immunology of stroke: from mechanisms
to translation. Nat Med. 2011;17:796808.
62. Weiss JM, Quan N, Sundar SK. Widespread activation and consequences
of interleukin-1in the brain. Ann N Y Acad Sci. 1994;741:338357.

Journal of Inflammation Research 2013:6

Inflammation and brain injury

63. Offner H, Vandenbark AA, Hurn PD. Effect of experimental
stroke on peripheral immunity: CNS ischemia induces profound
immunosuppression. Neuroscience. 2009;158:10981111.
64. Sundar SK, Becker KJ, Cierpial MA, et al. Intracerebroventricular
infusion of interleukin 1 rapidly decreases peripheral cellular immune
responses. Proc Natl Acad Sci U S A. 1989;86:63986402.
65. Catania A, Lonati C, Sordi A, Gatti S. Detrimental consequences of brain
injury on peripheral cells. Brain Behav Immun. 2009;23:877884.
66. Chamorro A, Amaro S, Vargas M, etal. Catecholamines, infection, and
death in acute ischemic stroke. J Neurol Sci. 2007;252:2935.
67. Bethin KE, Vogt SK, Muglia LJ. Interleukin-6 is an essential,
corticotropin-releasing hormone-independent stimulator of the adrenal
axis during immune system activation. Proc Natl Acad Sci U S A.
2000;97:93179322.
68. Smith CJ, Emsley HC, Udeh CT, etal. Interleukin-1 receptor antagonist
reverses stroke-associated peripheral immune suppression. Cytokine.
2012;58:384389.
69. Agnihotri S, Czap A, Staff I, Fortunato G, McCullough LD. Peripheral
leukocyte counts and outcomes after intracerebral hemorrhage.
J Neuroinflammation. 2011;8:160.
70. Dziedzic T, Bartus S, Klimkowicz A, Motyl M, Slowik A,
Szczudlik A. Intracerebral hemorrhage triggers interleukin-6 and
interleukin-10 release in blood. Stroke. 2002;33:23342335.
71. Brough D, Tyrrell PJ, Allan SM. Regulation of interleukin-1in acute
brain injury. Trends Pharmacol Sci. 2011;32:617622.
72. Ross J, Brough D, Gibson RM, Loddick SA, Rothwell NJ. A selective,
non-peptide caspase-1inhibitor, VRT-018858, markedly reduces brain
damage induced by transient ischemia in the rat. Neuropharmacology.
2007;53:638642.
73. Suzuki H, Sozen T, Hasegawa Y, Chen W, Zhang JH. Caspase-1inhibitor
prevents neurogenic pulmonary edema after subarachnoid hemorrhage
in mice. Stroke. 2009;40:38723875.
74. Wu B, Ma Q, Khatibi N, etal. Ac-YVAD-CMK decreases blood-brain
barrier degradation by inhibiting caspase-1 activation of interleukin1beta in intracerebral hemorrhage mouse model. Transl Stroke Res.
2010;1:5764.
75. Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y,
Kogure K. Interleukin-1 as a pathogenetic mediator of ischemic brain
damage in rats. Stroke. 1995;26:676680; discussion 681.
76. Pradillo JM, Denes A, Greenhalgh AD, etal. Delayed administration
of interleukin-1 receptor antagonist reduces ischemic brain damage and
inflammation in comorbid rats. J Cereb Blood Flow Metab. 2012;32:
18101819.
77. Emsley HC, Smith CJ, Georgiou RF, et al. A randomised phase II study
of interleukin-1 receptor antagonist in acute stroke patients. J Neurol
Neurosurg Psychiatry. 2005;76:13661372.
78. Clark SR, McMahon CJ, Gueorguieva I, etal. Interleukin-1 receptor
antagonist penetrates human brain at experimentally therapeutic
concentrations. J Cereb Blood Flow Metab. 2008;28:387394.
79. Gueorguieva I, Clark SR, McMahon CJ, et al. Pharmacokinetic
modelling of interleukin-1 receptor antagonist in plasma and
cerebrospinal fluid of patients following subarachnoid haemorrhage.
Br J Clin Pharmacol. 2008;65:317325.
80. Thomas S, Fell DA. The role of multiple enzyme activation in metabolic
flux control. Adv Enzyme Regul. 1998;38:6585.
81. Hopkins AL. Network pharmacology: the next paradigm in drug
discovery. Nat Chem Biol. 2008;4:682690.
82. Small BG, McColl BW, Allmendinger R, etal. Efficient discovery of
anti-inflammatory small-molecule combinations using evolutionary
computing. Nat Chem Biol. 2011;7:902908.

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