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Teresa
Binstock
Researcher in Developmental & Behavioral
Neuroanatomy
April 03, 2010
Increased levels of
high mobility group box 1 (HMGB1) have been reported in an autism
subgroup (3). HMGB1 is implicated in rheumatic diseases (2) and
seizures (11), activates astrocytes (1), and is reviewed (eg,
4-5). Quercetin may have therapeutic value (6) in some individuals
with autism wherein abnormal responses to LPS have been reported
(7-10; see also 11-12).
References:
1.
Selective
proinflammatory activation of astrocytes by high-mobility group
box 1 protein signaling
Pedrazzi
M, Patrone M, Passalacqua M, Ranzato E, Colamassaro D, Sparatore
B, Pontremoli S, Melloni E.
Department of Experimental
Medicine-Biochemistry Section and Centre of Excellence for
Biomedical Research, University of Genoa, Viale Benedetto XV,
Genoa, Italy. marcopedraz@libero.it
J
Immunol. 2007 Dec
15;179(12):8525-32.
http://www.jimmunol.org/cgi/reprint/179/12/8525
Extracellular
high-mobility group box 1 protein (HMGB1) triggers inflammatory
events in the brain. We demonstrate that astrocytes, the main
glial cells in the brain, acquire a specific reactive phenotype
when exposed to HMGB1. This cell activation, which involves the
receptor for advanced glycation end-products and the MAPK/ERK1/2
cascade, results in the transcriptional/translational induction of
a restricted number of inflammatory mediators, including
cyclooxygenase-2, matrix metalloproteinase-9, and several
chemokines of the CC and CXC families. The mixture of factors
released by HMGB1-reactive astrocytes displays a potent
chemotactic activity on human monocytic cells. This study is the
first to suggest that HMGB1/astrocyte interaction plays a specific
functional role in the progression of inflammatory processes in
the CNS by facilitating local leukocyte infiltration.
2.
High-mobility
group box protein 1 (HMGB1): an alarmin mediating the pathogenesis
of rheumatic disease
Pisetsky
DS, Erlandsson-Harris H, Andersson U.
Arthritis Res Ther.
2008;10(3):209. Epub 2008 Jun
30.
http://arthritis-research.com/content/pdf/ar2440.pdf
High-mobility
group box protein 1 (HMGB1) is a non-histone nuclear protein that
has a dual function. Inside the cell, HMGB1 binds DNA, regulating
transcription and determining chromosomal architecture. Outside
the cell, HMGB1 can serve as an alarmin to activate the innate
system and mediate a wide range of physiological and pathological
responses. To function as an alarmin, HMGB1 translocates from the
nucleus of the cell to the extra-cellular milieu, a process that
can take place with cell activation as well as cell death. HMGB1
can interact with receptors that include RAGE (receptor for
advanced glycation endproducts) as well as Toll-like receptor-2
(TLR-2) and TLR-4 and function in a synergistic fashion with other
proinflammatory mediators to induce responses. As shown in studies
on patients as well as animal models, HMGB1 can play an important
role in the pathogenesis of rheumatic disease, including
rheumatoid arthritis, systemic lupus erythematosus, and
polymyositis among others. New approaches to therapy for these
diseases may involve strategies to inhibit HMGB1 release from
cells, its interaction with receptors, and downstream
signaling.
3. Increased
serum levels of high mobility group box 1 protein in patients with
autistic disorder
Emanuele
E, Boso M, Brondino N, Pietra S, Barale F, Ucelli di Nemi S,
Politi P.
Department of Health Sciences, Section of Psychiatry,
University of Pavia, Via Bassi, 21, I-27100, Pavia, Italy.
Prog
Neuropsychopharmacol Biol Psychiatry. 2010 Mar 17. [Epub ahead of
print]
$
http://linkinghub.elsevier.com/retrieve/pii/S0278-5846(10)00113-2
BACKGROUND:
High mobility group box 1 (HMGB1) is a highly conserved,
ubiquitous protein that functions as an activator for inducing the
immune response and can be released from neurons after glutamate
excitotoxicity. The objective of the present study was to measure
serum levels of HMGB1 in patients with autistic disorder and to
study their relationship with clinical characteristics. METHODS:
We enrolled 22 adult patients with autistic disorder (mean age:
28.1+/-7.7years) and 28 age- and gender-matched healthy controls
(mean age: 28.7+/-8.1years). Serum levels of HMGB1 were measured
by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared
with healthy subjects, serum levels of HMGB1 were significantly
higher in patients with autistic disorder (10.8+/-2.6ng/mL versus
5.6+/-2.5ng/mL, respectively, P<0.001). After adjustment for
potential confounders, serum HMGB1 levels were independently
associated with their domain A scores in the Autism Diagnostic
Interview-Revised, which reflects their impairments in social
interaction. CONCLUSIONS: These results suggest that HMGB1 levels
may be affected in autistic disorder. Increased HMGB1 may be a
biological correlate of the impaired reciprocal social
interactions in this neurodevelopmental disorder.
4.
HMGB1: endogenous
danger signaling
Klune JR,
Dhupar R, Cardinal J, Billiar TR, Tsung A.
Department of
Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania,
USA.
Mol Med. 2008
Jul-Aug;14(7-8):476-84.
http://www.molmed.org/pdfstore/476_484.Klune.00034.PDF
While
foreign pathogens and their products have long been known to
activate the innate immune system, the recent recognition of a
group of endogenous molecules that serve a similar function has
provided a framework for understanding the overlap between the
inflammatory responses activated by pathogens and injury. These
endogenous molecules, termed alarmins, are normal cell
constituents that can be released into the extracellular milieu
during states of cellular stress or damage and subsequently
activate the immune system. One nuclear protein, High mobility
group box-1 (HMGB1), has received particular attention as
fulfilling the functions of an alarmin by being involved in both
infectious and non-infectious inflammatory conditions. Once
released, HMGB1 signals through various receptors to activate
immune cells involved in the immune process. Although initial
studies demonstrated HMGB1 as a late mediator of sepsis, recent
findings indicate HMGB1 to have an important role in models of
non-infectious inflammation, such as autoimmunity, cancer, trauma,
and ischemia reperfusion injury. Furthermore, in contrast to its
pro-inflammatory functions, there is evidence that HMGB1 also has
restorative effects leading to tissue repair and regeneration. The
complex functions of HMGB1 as an archetypical alarmin are outlined
here to review our current understanding of a molecule that holds
the potential for treatment in many important human
conditions.
5. HMGB1
preconditioning: therapeutic application for a danger
signal?
Klune JR, Billiar
TR, Tsung A.
Department of Surgery, University of Pittsburgh
School of Medicine, 200 Lothrop Street, Presbyterian Hospital
F1200, Pittsburgh, PA 15213, USA.
J Leukoc Biol. 2008
Mar;83(3):558-63. Epub 2007 Oct
15.
http://www.jleukbio.org/cgi/content/full/83/3/558
High
mobility group box 1 (HMGB1) is a nuclear factor released
extracellularly as a late mediator of lethality in sepsis and as
an early mediator of inflammation following injury. In contrast to
the proinflammatory role of HMGB1, recent evidence suggests
beneficial applications of HMGB1 in injury states. One such
application is the use of HMGB1 as a preconditioning stimulus.
Preconditioning is a phenomenon whereby a low level of stressful
stimuli confers protection against subsequent injury.
Preconditioning has been demonstrated in multiple species, can be
induced by various stimuli, and is applicable in different organ
systems. Only with the recent introduction of the concept of
endogenous molecules, such as HMGB1, as signals and mediators for
inflammation during injury states has the use of endogenous
molecules been investigated for this use. This review will focus
on the use of endogenous molecules, specifically HMGB1, as a
preconditioning stimulus and its mechanism of protection, as well
as other protective applications for HMGB1.
6.
Quercetin prevents
LPS-induced high-mobility group box 1 release and proinflammatory
function
Tang D, Kang R,
Xiao W, Zhang H, Lotze MT, Wang H, Xiao X.
Laboratory of Shock,
Department of Pathophysiology, Xiangya School of Medicine,
Changsha, Hunan, People's Republic of China.
Am J Respir Cell
Mol Biol. 2009 Dec;41(6):651-60. Epub 2009 Mar 5.
$ for awhile:
http://ajrcmb.atsjournals.org/cgi/content/full/41/6/651
The
pathogenesis of sepsis is mediated in part by the
pathogen-associated molecular pattern molecule bacterial
endotoxin, which stimulates macrophages to sequentially release
early (e.g., TNF-alpha, IL-1beta) and late (e.g., high-mobility
group box [HMGB] 1 protein) proinflammatory mediators. The recent
discovery of HMGB1 as a late mediator of lethal sepsis has
prompted investigation into development of several new
experimental therapeutics that limit release, either blocking
HMGB1 itself or its nominal receptors. Quercetin was recently
identified as an experimental therapeutic that significantly
protects against oxidative injury. Here, we report that quercetin
attenuates lethal systemic inflammation caused by endotoxemia,
even if treatment is started after the early TNF response.
Quercetin treatment reduced circulating levels of HMGB1 in animals
with established endotoxemia. In macrophage cultures, quercetin
inhibited release as well as the cytokine activities of HMGB1,
including limiting the activation of mitogen-activated protein
kinase and NF-kappaB, two signaling pathways that are critical for
HMGB1-induced subsequent cytokine release. Quercetin and
autophagic inhibitor, wortmannin, inhibited LPS-induced type-II
microtubule-associated protein 1A/1B-light chain 3 production and
aggregation, as well as HMGB1 translocation and release,
suggesting a potential association between autophagy and HMGB1
release. Quercetin delivery, a strategy to pharmacologically
inhibit HMGB1 release that is effective at clinically achievable
concentrations, now warrants further evaluation in sepsis and
other systemic inflammatory disorders.
7. Differential
monocyte responses to TLR ligands in children with autism spectrum
disorders
Enstrom AM, Onore
CE, Van de Water JA, Ashwood P.
Departments of Medical
Microbiology and Immunology, University of California at Davis, CA
95817, USA.
Brain Behav Immun. 2010 Jan;24(1):64-71.
$
http://linkinghub.elsevier.com/retrieve/pii/S0889-1591(09)00388-2
Autism
spectrum disorders (ASD) are characterized by impairment in social
interactions, communication deficits, and restricted repetitive
interests and behaviors. Recent evidence has suggested that
impairments of innate immunity may play an important role in ASD.
To test this hypothesis, we isolated peripheral blood monocytes
from 17 children with ASD and 16 age-matched typically developing
(TD) controls and stimulated these cell cultures in vitro with
distinct toll-like receptors (TLR) ligands: TLR 2 (lipoteichoic
acid; LTA), TLR 3 (poly I:C), TLR
4 (lipopolysaccharide;
LPS),
TLR 5 (flagellin), and TLR 9 (CpG-B). Supernatants were harvested
from the cell cultures and pro-inflammatory cytokine responses for
IL-1beta, IL-6, IL-8, TNFalpha, MCP-1, and GM-CSF were determined
by multiplex Luminex analysis. After in vitro challenge with TLR
ligands, differential cytokine responses were observed in monocyte
cultures from children with ASD compared with TD control children.
In particular, there was a marked increase in pro-inflammatory
IL-1beta, IL-6, and TNFalpha responses following TLR 2, and
IL-1beta response
following TLR 4 stimulation in monocyte cultures from children
with ASD (p<0.04).
Conversely, following TLR 9 stimulation there was a decrease in
IL-1beta, IL-6, GM-CSF, and TNFalpha responses in monocyte cell
cultures from children with ASD compared with controls (p<0.05).
These data indicate that, monocyte cultures from children with ASD
are more responsive to signaling via select TLRs. As monocytes are
key regulators of the immune response, dysfunction in the response
of these cells could result in long-term immune alterations in
children with ASD that may lead to the development of adverse
neuroimmune interactions and could play a role in the
pathophysiology observed in ASD.
8. Innate
immunity associated with inflammatory responses and cytokine
production against common dietary proteins in patients with autism
spectrum disorder
Jyonouchi
H, Sun S, Itokazu N.
Department of Pediatrics, University of
Minnesota, Minneapolis, Minn, USA.
Neuropsychobiology.
2002;46(2):76-84.
$
http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=nps46076
OBJECTIVES:
Children with autism spectrum disorder (ASD) frequently reveal
various gastrointestinal (GI) symptoms that may resolve with an
elimination diet along with apparent improvement of some of the
behavioral symptoms. Evidence suggests that ASD may be accompanied
by aberrant (inflammatory) innate immune responses. This may
predispose ASD children to sensitization to common dietary
proteins (DP), leading to GI inflammation and aggravation of some
behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and
TNF-alpha production against representative DPs [gliadin, cow's
milk protein (CMP), and soy] by peripheral blood mononuclear cells
(PBMCs) from ASD and control children [those with DP intolerance
(DPI), ASD siblings, and healthy unrelated children]. We evaluated
the results in association with proinflammatory and
counter-regulatory cytokine production with endotoxin (LPS), a
microbial product of intestinal flora and a surrogate stimulant
for innate immune responses. RESULTS: ASD PBMCs produced elevated
IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high
frequency as observed in DPI PBMCs. ASD
PBMCs revealed increased proinflammatory cytokine responses with
LPS at high frequency with positive correlation between
proinflammatory cytokine production with LPS and IFN-gamma and
TNF-alpha production against DPs.
Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune
reactivity to DPs may be associated with apparent DPI and GI
inflammation in ASD children that may be partly associated with
aberrant innate immune response against endotoxin, a product of
the gut bacteria.
9. Preliminary
evidence of the in vitro effects of BDE-47 on innate immune
responses in children with autism spectrum disorders
Ashwood
P, Schauer J, Pessah IN, Van de Water J.
Department of Medical
Microbiology and Immunology, University of California, Davis, CA
95616, USA.
J Neuroimmunol. 2009 Mar 31;208(1-2):130-5. Epub
2009 Feb
10.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692510/pdf/nihms108073.pdf
Autism
spectrum disorders (ASD) are complex neurodevelopmental disorders
that manifest in childhood. Immune dysregulation and autoimmune
reactivity may contribute to the etiology of ASD and are likely
the result of both genetic and environmental susceptibilities. A
common environmental contaminant, 2,2',4,4'-tetrabrominated
biphenyl (BDE-47), was tested for differential effects on the
immune response of peripheral blood mononuclear cells (PBMC)
isolated from children with ASD (n=19) and age-matched typically
developing controls (TD, n=18). PBMC were exposed in vitro to
either 100 nM or 500 nM BDE-47, before challenge with bacterial
lipopolysaccharide (LPS), an innate immune activator, with
resultant cytokine production measured using the Luminex multiplex
platform. The
cytokine responses of LPS stimulated PBMC from ASD and TD subjects
diverged in the presence of 100 nM BDE.
For example, cells cultured from the TD group demonstrated
significantly decreased levels of the cytokines IL-12p40, GM-CSF,
IL-6, TNFalpha, and the chemokines MIP-1alpha and MIP-1beta
following LPS stimulation of PBMC pretreated with 100 nM BDE-47
compared with samples treated with vehicle control (p<0.05). In
contrast, cells
cultured from subjects with ASD demonstrated an increased IL-1beta
response to LPS (p=0.033) when
pretreated with 100 nM BDE-47
compared with vehicle control. Preincubation with 500 nM BDE-47
significantly increased the stimulated release of the inflammatory
chemokine IL-8 (p<0.04) in cells cultured from subjects with
ASD but not in cells from TD controls. These data suggest that in
vitro exposure of PBMC to BDE-47 affects cell cytokine production
in a pediatric population. Moreover, PBMC from the ASD subjects
were differentially affected when compared with the TD controls
suggesting a biological basis for altered sensitivity to BDE-47 in
the ASD population.
10. Low-grade
endotoxemia in patients with severe autism
Emanuele
E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, di Nemi SU,
Politi P.
Neurosci Lett. 2010 Mar 8;471(3):162-5. Epub 2010 Jan
25.
$
http://linkinghub.elsevier.com/retrieve/pii/S0304-3940(10)00061-3
The
objective of this study was to examine whether levels of endotoxin
and other markers of immuno-inflammatory activation are altered in
adult patients with severe autism. We determined circulating serum
endotoxin levels, its soluble receptor (sCD14), and markers of
immuno-inflammatory activation (IL-1beta, IL-6, and IL-10) in 22
adult patients with severe autism and 28 age- and gender-matched
healthy controls. Compared with healthy subjects, serum levels of
endotoxin were significantly higher in autistic patients and
inversely and independently correlated with Socialization scores
on the Vineland Adaptive Behavior Scales (VABS) and ADI-R Domain A
score (social). Whether increased endotoxin may contribute to the
pathophysiology of inflammation and impaired reciprocal social
interaction in autism should be further explored in future
studies.
11. Toll-like
receptor 4 and high-mobility group box-1 are involved in
ictogenesis and can be targeted to reduce seizures.
Maroso
M et al.
Department of Neuroscience, Mario Negri Institute for
Pharmacological Research, Milano, Italy.
Nat Med. 2010 Mar 28.
[Epub ahead of print]
http://dx.doi.org/10.1038/nm.2127
Brain
inflammation is a major factor in epilepsy, but the impact of
specific inflammatory mediators on neuronal excitability is
incompletely understood. Using models of acute and chronic
seizures in C57BL/6 mice, we discovered a proconvulsant pathway
involving high-mobility group box-1 (HMGB1) release from neurons
and glia and its interaction with Toll-like receptor 4 (TLR4), a
key receptor of innate immunity. Antagonists of HMGB1 and TLR4
retard seizure precipitation and decrease acute and chronic
seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to
kainate-induced seizures. The proconvulsant effects of HMGB1, like
those of interleukin-1beta (IL-1beta), are partly mediated by
ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors.
Increased expression of HMGB1 and TLR4 in human epileptogenic
tissue, like that observed in the mouse model of chronic seizures,
suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus,
HMGB1-TLR4 signaling may contribute to generating and perpetuating
seizures in humans and might be targeted to attain anticonvulsant
effects in epilepsies that are currently resistant to drugs.
12.
The alarmin HMGB1
acts in synergy with endogenous and exogenous danger signals to
promote inflammation.
Hreggvidsdottir
HS, Ostberg T, Wähämaa H, Schierbeck H, Aveberger AC,
Klevenvall L, Palmblad K, Ottosson L, Andersson U, Harris
HE.
Department of Medicine, Rheumatology Research Unit,
Karolinska Hospital, Karolinska Institutet, S-171 76 Stockholm,
Sweden.
J Leukoc Biol. 2009 Sep;86(3):655-62. Epub 2009 Jun
29.
$ for awhile
http://www.jleukbio.org/cgi/content/full/86/3/655
The
nuclear protein HMGB1 has previously been demonstrated to act as
an alarmin and to promote inflammation upon extracellular release,
yet its mode of action is still not well defined. Access to highly
purified HMGB1 preparations from prokaryotic and eukaryotic
sources enabled studies of activation of human PBMC or synovial
fibroblast cultures in response to HMGB1 alone or after binding to
cofactors. HMGB1 on its own could not induce detectable IL-6
production. However, strong
enhancing effects on induction of proinflammatory cytokine
production occurred when the protein associated with each of the
separate proinflammatory molecules,
rhIL-1beta, the
TLR4 ligand LPS, the TLR9
ligand CpG-ODN, or the TLR1-TLR2 ligand Pam3CSK4. The
bioactivities were recorded in cocultures with preformed HMGB1
complexes but not after sequential or simultaneous addition of
HMGB1 and the individual ligands. Individual A-box and B-box
domains of HMGB1 had the ability to bind LPS and enhance IL-6
production. Heat denaturation of HMGB1 eliminated this
enhancement. Cocultures with HMGB1 and other proinflammatory
molecules such as TNF, RANKL, or IL-18 did not induce enhancement.
HMGB1 thus acts
broadly with many but not all immunostimulatory molecules to
amplify their activity in a synergistic manner.
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Teresa Binstock by email
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