LPS ON MICROGLIA
Oxígeno, Oxido Nítrico y perspectivas terapéuticas
Simposio Internacional, Academia Nacional de Medicina
Buenos Aires, 30 abril 1998
of microglia activation by lipopolysaccharide and reactive oxygen
species generation in septic shock and central nervous system
pathologies: a review
Department of Pharmacology,
Chicago College of Osteopathic Medicine, Midwestern University,
Downers Grove, Illinois, USA
Key words: microglia, lipopolysaccharide, reactive oxygen
species, superoxide, sepsis, shock, therapy, review.
pathophysiology of organ system failure in sepsis, in particular the
effects of septic shock on the central nervous system, are still
incompletely understood. Lipopolysaccharide(LPS) from Gram-negative
bacteria affects the permeability of the blood-brain barrier and
causes the activation of brain microglia. A growing body of research
supports involvement of activated brain microglia in brain pathologies
caused by infectious diseases, trauma, tumors, ischemia, Alzheimer’s
disease, Parkinson’s disease, Down’s syndrome, multiple sclerosis
and AIDS. Those seminal studies that have contributed to the
characterization of the in vivo and in vitro effects of LPS on
microglia function, mediator generation and receptor expression are
presented within a historical perspective. In particular, all those in
vitro studies on O2-, H2O2 and NO· generation by either unprimed or
primed microglia have been extensively reviewed. The apparent
controversial effect of LPS on microglia O2- is discussed. Because
treatment modalities for septic shock have not significantly affected
the current high mortality, alternative strategies with antioxidants
are currently being investigated. Reduction of microglia O2-
generation is proposed as a possible complementary strategy to
antioxidative therapy for septic shock and CNS pathologies that
involve activated microglia.
terapéutica de la activación de la microglia por lipopolisacárido y
la generación de especies reactivas del oxígeno en el shock séptico
y en patologías del sistema nervioso central: una revisión. En la
actualidad no se hallan completamente establecidos los efectos del
shock séptico sobre el sistema nervioso central(SNC). El
lipopolisacárido(LPS) de bacterias Gram-negativas puede afectar la
permeabilidad de la barrera hematoencefálica y causar la activación
de la microglia en el SNC. Un creciente numero de investigaciones ha
documentado el rol de la microglia activada en patologías del SNC
causadas por diversos agentes infecciosos, trauma, tumores, isquemia,
enfermedad de Alzheimer, síndrome de Down, esclerosis múltiple y
síndrome de inmunodeficiencia adquirida. Se presenta una revisión de
aquellos estudios, que desde una perspectiva histórica han
contribuido a la caracterización de los efectos in vitro e in vivo
del LPS sobre la activación de la microglia, la generación de
mediadores y la expresión de receptores. En particular, se ha
completado una detallada revisión de estudios in vitro sobre la
generación de especies reactivas del oxígeno (ROS), en particular,
O2-, H2O2 y NO· por parte de microglia activada o no activada. El
aparente efecto contradictorio del LPS sobre la producción de O2- por
parte de la microglia de rata ha sido comentado. Debido a que el
tratamiento clínico actual del shock séptico no ha logrado disminuir
la mortalidad de manera significativa, en la actualidad se investigan
tratamientos alternativos. Un área de interés es el uso de
antioxidantes para eliminar las ROS. Se propone que una alternativa al
uso de antioxidantes es inhibir la generación del ROS por la
microglia activada. Esta terapia alternativa podría afectar
significativamente el tratamiento del shock séptico y de otras
patologías del SNC.
Postal address: Dr. Alejandro M.S. Mayer, Department of
Pharmacology, Chicago College of Osteopathic Medicine, Midwestern
University, 555 31st Street, Downers Grove, Illinois 60515, USA. Fax:
630 - 971-6414; E-mail: email@example.com
Distributive shock, lipopolysaccharide and the septic mediator
Shock is a complex clinical syndrome that regardless of etiology
causes a profound reduction in tissue perfusion with inadequate
delivery of oxygen to the brain and other vital organs1. Septic shock,
a type of distributive shock characterized by massive arteriovenous
dilation, is presently the leading cause of death in intensive care
units and the thirteenth most common cause of death in the US2.
Despite the importance to the outcome of septic shock, the
pathophysiology of organ system failure and in particular the effects
of sepsis on the central nervous system (CNS), one of the first organs
to be affected by sepsis, are still incompletely understood3. Although
septic shock may be caused by systemic infections with bacterial,
fungal, mycobacterial, rickettsial, protozoal or viral organisms, the
majority of clinical cases involve aerobic or anaerobic Gram-negative
bacteremia. The latter are usually associated with nosocomial
infections arising from urinary, gastrointestinal and respiratory
tract infections by organisms like Escherichia coli, Klebsiella
pneumoniae, Enterobacter-Serratia species, Proteus species and
Pseudomonas aeruginosa4. Infections by Gram-negative bacteria like E.
coli as well as Gram- positive organisms such as Streptococcus
pneumoniae, cause inflammation in the subarachnoid space of the brain,
the pathological hallmark of bacterial meningitis. This is a common
neonatal worldwide disease that still has high mortality despite the
availability of antimicrobial therapy5, 6. Gram-negative bacteria
elicit systemic as well as CNS intrathecal inflammatory responses by
releasing a structural component of their cell wall, namely
lipopolysaccharide (LPS)7. As a bacterial factor, LPS was first
isolated from Vibrio cholerae 106 years ago8. LPS can systemically
activate endothelial cells, platelets, macrophage-monocytes and
neutrophils to produce and release numerous endogenous mediators,
including reactive oxygen intermediates (ROS) 9, 10, collectively
known as the septic cascade. In the CNS, LPS- induced inflammation in
the subarachnoid space leads to disruption of the blood-brain
barrier11, 12, attraction of blood-derived leukocytes, release of
inflammatory and neurotoxic mediators and activation of brain
microglia5, 6, 13. Although a complete description of causal
relationships between inflammatory mediators and clinical
manifestations in septic shock remains to be fully elucidated, there
is at present sufficient clinical and experimental evidence that
septic inflammatory mediators, including ROS, are mainly responsible
for the cardiovascular, pulmonary and CNS effects observed2.
The role of ROS in septic shock and other central nervous system
In septic shock14 as well as in other CNS pathologies, such as
Parkinson’s disease15, Alzheimer’s disease15, Down’s syndrome16,
cerebral ischemia and reperfusion17, 18, amyotrophic lateral
sclerosis19 and multiple sclerosis20 the generation of excessive
quantitities of inflammatory cytokines13 such as, e.g. tumor necrosis
factor-a21, interleukin-122, 23 as well as ROS17 and NO·24 has been
well documented. There appear to be several potential mechanisms that
could lead to the generation of ROS in the CNS : (1) mitochondrial
electron transport chain electron bleed, (2) eicosanoid metabolism,
(3) autooxidation of catecholamines, (4) xanthine oxidase and (5) the
respiratory burst of activated leukocytes14, 17, 18. Generation of ROS
by the first four mechanisms has received intense scrutiny by
investigators over the past 20 years, with the use of a wide variety
of techniques14. But generation of ROS by CNS leukocytes, i.e.
infiltrating neutrophils and monocytes as well as resident microglia
production of superoxide anion (O2-), hydrogen peroxide (H2O2) and
nitric oxide (NO·) in the CNS, has only received notable attention
since the mid-1980’s25-27 (Table 1 and 2). The underlying
pathophysiological effects of ROS in these CNS pathologies, in
particular those related to the production of the radical O2- and the
non-radical H2O2, have been shown to result from DNA strand breaks,
protein alterations and the formation of lipid hydroperoxides which
may disrupt membrane function as well as membrane-bound enzymes and
receptors14, 17, 18, 20. Because the brain is rich in iron content28
ROS injury to brain cells could potentially result in iron ion
release, further free radical formation and damage to neurons,
particularly their synapses29 as well as to oligodendrocytes, the
myelin producing cell of the central nervous system30. Interestingly
ROS do not seem to affect microglia or astrocytes31. Prolonged
exposure to ROS could override normal CNS antioxidant defense
mechanisms, e.g. superoxide dismutase, catalase,
glutathione-S-transferase, glutathione peroxidase, permanently
affecting cellular function32. Finally, although excessive production
of ROS can lead to CNS pathology, ROS do fulfill physiological
functions in the brain where they appear to be involved in
intracellular signalling33 as well as normal CNS metabolism15, 34.
Microglia activation by LPS and the generation of ROS
It has been known for more than 25 years35 that activated
phagocytes such as monocytes, tissue macropha-ges, neutrophils and
eosinophils are able to generate ROS. Since 1986, numerous studies
have shown that the leukocyte-dependent source of O2- in the CNS is
the microglia, the brain resident macrophage (Table 2). Microglia are
leukocytes derived from outside the CNS, and as first proposed by Del
Rio Hortega36 in 1932, they are formed in the bone marrow, then enter
the circulation as monocytes and migrate into the brain during late
embryonic life establishing permanent residency37. Histological
studies have shown that in the normal brain microglia are of two
types, ameboid microglia found in perinatal CNS and ramified microglia
found throughout the gray and white parenchyma of the adult CNS. The
historical controversies regarding the origin of the microglia have
been extensively reviewed37, 38, 39 . Microglia activation in brain
pathologies, as caused by infectious diseases, inflammation, trauma,
brain tumors, ischemia and AIDS, may result in neuronal injury and
ultimately neurodegeneration40, 41, 42, 43, 44. Similar to other
tissue macrophages, when activated microglia release a large number of
secretory products35, 45, 46, followed by sublethal and lethal injury
to the CNS. Two different phenotypic forms of microglia appear, the
activated but nonphago-cytic microglia in inflammatory pathologies and
the reactive or phagocytic microglia in trauma, infection and neuronal
degeneration. Both appear to have the capacity to express cell-surface
receptors and release biologically active substances known to be
mediators of inflammation, such as cytokines, coagulation factors,
complement factors, eicosanoids, proteases, ROS and NO· 44,47.
One of the activators of microglia ROS generation that has received
growing attention over the past 5 years is LPS9. LPS potently
activates macrophages mediator generation via the lipid A portion of
the macromolecule48. Similar to Kupffer cells49,50, unstimulated
parenchymal brain microglia appear to be downregulated in terms of
endocytic, cell surface receptor expression 51 and ROS generation52.
However, LPS as well as the mediators elicited by LPS in septic shock,
have been shown to affect permeability of the brain microvasculature
6,12,22,53, and to induce activation of brain microglia in vivo 54.
The publications listed in Table 1 document in historical order the
earliest published reports of in vivo53-60 and in vitro 60-93 effects
of LPS on the activation of microglia effector functions. These
functions include cytotoxicity61,81,90, antigen expression66,78,91,92,
growth inhibition62, ion channels74, cytoskeletal changes72, 77,
bacterial digestion88 and possibly apoptosis93. Furthermore, once
activated microglia generate a vast array of mediators that include
growth factors63, 87, ROS76, NO·85, 87, 97, complement70, 87,
proteases67, 79, 84, excitatory aminoacids75, arachidonic acid
derivatives62, 82 and cytokines60, 64, 68, 71, 73, 80, 86, 89,
possibly by affecting microglia signal transduction mechanisms83. A
similar historical perspective was used to prepare Table 2 which
clearly demonstrates that since 198625, when microglia were first
shown to have the same capacity as other macrophages to generate O2-,
there has been a great interest in characterizing the mechanism of ROS
generation by this brain phagocyte. During the past 12 years, numerous
research groups have shown that O2-, H2O2 and NO· are generated by
microglia isolated from rats 25, 26, 52, 65, 95, 97, 100-102, 104-106,
109, 111-113, 115, 116, 118, 120, 121, mi-ce27, 76, 98, 99, 103, 114,
117, hamsters114, dogs96, swine108 and humans107, 108, 110, 114, 119,
when stimulated with a variety of agonists such as phorbol ester25-27,
52, 76, 95, 98, 100, 102, 104,106-108, 113, 115, 116, 118, opsonized
zymosan26, 27, 100, 103, 114, 118, calcium ionophore105, antiviral
antibodies96, antibody-coated red blood cells27, LDL111 and myelin112.
Furthermore, these studies have clearly demonstrated that
unprimed25-27, 96, 98, 102, 104, 105, 111, 112 microglia in vitro ROS
generation is enhanced when these phagocytes are primed with
interferon a, b and g.95, 99, 100, 107, 108, 110, 119,
TNF-a107,108,110,114, interleukin-1110, 114, 119 , b-amyloid 109, 113,
118, albumin115 and LPS52, 65, 76, 101, 103, 106, 108, 113, 114, 116,
117, 120, 121 prior to agonist stimulation .
Interestingly, the effect of LPS on in vitro generation of
agonist-stimulated microglia O2- generation appears to be
controversial. While Colton et al.106 reported that « LPS does not
affect O2- production in rat microglia «, other investigators have
reported that LPS primes mouse76 and rat113 microglia for enhanced
PMA-stimulated O2- release. Our recent report confirms these two
studies52. Furthermore, we have observed that LPS concentrations
greater than 3 ng/ml will exert a cytotoxic effect on neonatal
microglia52 in vitro. Thus far, our experimental results suggest that
LPS has a biphasic in vitro effect on microglia O2- generation: at
concentrations lower than 3 ng/ml, LPS potently and dose-dependently
primes PMA-stimulated O2- generation; however, at concentrations
greater than 3ng/ml, LPS appears to inhibit PMA-stimulated O2-
generation. Concomitant with this inhibition of O2- generation, we
have measured enhanced release of NO·, TNF-a, thromboxane B2,
metalloproteinases MMP-9 and LDH, as well as apoptosis93. Since
differences in O2- generation have been reported in human, mice and
hamster microglia114, determining if LPS’s biphasic effects on rat
microglia will also occur in microglia of other species, particularly
in human microglia, appears to be an important question that needs to
be answered. Systemic administration of LPS activates rat microglial
cells54 in the hypothalamus, thalamus and brainstem. In human
pathologies like septic shock and bacterial meningitis, if microglia,
once activated release mediators such as TNF-a, potential toxicity
could result to neurons, oligodendrocytes and astrocytes. Finally,
determining if microglia ROS generation will be activated in
experimental sepsis with the more virulent strains of E. coli,
serotypes that can survive and disseminate outside the intestine and
ultimately cause human septicemia, needs to be addressed2, 122.
Interestingly, none of the publications listed in Tables 1 or 2 used
E. coli LPS derived from the virulent strains2, 122.
Alternative therapeutic strategies for septic shock and the
modulation of microglia ROS generation
Since certain areas of the brain are rich in the transition metal
iron and microglia O2- has been shown to release iron from ferritin94,
H2O2 may combine with Fe2+ ions to form the highly reactive ·OH123,
which can then initiate multiple cellular lesions124,20. Microglia
have also been shown to release NO·65, which can react with O2- to
form peroxynitrite125 at a rate constant that is three times faster
than the rate at which superoxide dismutase scavenges O2-.
Peroxynitrite is a powerful oxidant that has been shown to oxidize
sulfhydryl groups, lipids, DNA and proteins125. However, O2-, H2O2 and
·OH normally have potent bactericidal functions, and thus the
generation of microglia ROS under physiological conditions, when NO·
concentration is 100-fold lower than that of superoxide dismutase,
could serve to protect the CNS against infectious organisms, ie.
bacteria, fungi and viruses 33,125,126.
Current treatment for septic shock includes antimicrobial
chemotherapy, radiologic and surgical procedures, volume replacement,
inotropic and vasoconstrictor support, oxygen therapy , mechanical
ventilation as well as hemodialysis and hemofiltration1 . However,
these treatments appear to have been unsuccessful in diminishing the
high mortality associated with septic shock2,127, 128. Since 1987, 12
prospective, placebo-controlled, rando-mized, double-blind,
multicenter trials involving a total of 6266 patients with
gram-negative sepsis have failed to demonstrate clinical efficacy of
these and other treatment strategies including methylprednisolone,
anti-LPS antibodies, platelet-activating factor-receptor antagonist,
recombinant human IL-1 receptor antagonist, anti-TNF antibodies and
ibuprofen2. Another strategy being investigated for septic shock is
antioxidative therapy129, which is also being extensively studied for
treatment of neurological infections130 and other CNS pathologies131
where ROS have been implicated. However, if as discussed earlier under
pathological conditions like septic shock, NO· is produced in
sufficient quantities so that it can physiologically outcompete
superoxide dismutase for O2-, production of significant amounts of
peroxynitrite125 would occur, as opposed to dismutation of O2- to
H2O2. It would therefore seem reasonable to conclude that enhanced
microglia O2- generation in brain pathologies will be only partially
modulated by the use of antioxidants that scavenge ROS. Alternative
pharmacological strategies, specifically targeted to turn off or
reduce rather than scavenge microglia O2-, by targeting signal
transduction pathways leading to NADPH oxidase activation, might be a
better approach that may hold considerable clinical promise. Why
modulate micro- glia generation of O2- as opposed to simply scavenging
ROS ? As explained earlier, modulation of O2- may help preserve
physiological levels of ROS which are necessary for the role of the
microglia in the defense of the brain126 and antioxidants such as SOD
may be unable to prevent rapid formation of peroxynitrite in brain
pathologies where NO· production is elevated thus fail to protect
against damage to neurons and other cells in the brain125. The
reduction of O2- generation in LPS-activated leukocytes by targeting
signal transduction pathways leading to O2- generation has been
studied in rat PMN132, rat Kupffer cells50, rat alveolar
macrophages133 and recently in retinoic acid-activated human
promyelocytic leukemia cells134. Although scavenging ROS is certainly
a potential treatment for activated microglia135, reducing the
generation of NADPH-dependent respiratory burst oxidase-dependent
ROS134 might be a particularly useful approach in those conditions
where microglia are primed for enhanced O2- generation136. Hopefully,
in the future the combination of these two approaches will contribute
to the successful development of alternative therapies for septic
shock and brain pathologies that involve activated microglia and the
generation of ROS.
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Table 1: Effects of LPS on microglia function, mediator generation and
a historical perspective
Year Species LPS Study completed Effect on Reference
In vitro In vivo
1986 Rat E. coli (NR) x IL-1 Giulian60
1987 Mice E. coli (NR) x Tumor cytotoxicity Frei61
1989 Rat S. typhimurium x Growth Gebicke62
1989 Rat S. typhimurium x PGE2 Gebicke62
1989 Rat NR x NGF Mallat63
1989 Mouse NR x TNF-a Sawada64
1992 Mice S. abortus equi x Activation Andersson55
1992 Rat NR x NO· Boje65
1992 Mice NR x CD4 receptor Sawada66
1992 Rat E. coli (NR) x Elastase Nakajima67
1992 Rat NR x IL-1 Yao68
1992 Rat E. coli 055 B5 x IL-1 Van Dam56
1993 Mice E. coli 0111:B4 x Toxoplasma gondii Chao69
1993 Mice E. coli 0111:B4 x C3 Haga70
1993 Human E. coli 055:B5 x IL-1; IL-6, TNF-a Lee71
1994 Rat NR x Ca2+/Actin Bader72
1994 Mice NR x MSR Receptor Bell57
1994 Mice NR x IL-10 Mizuno73
1994 Rat S. typhimurium x K+ channels Norenberg74
1994 Rat/mouse E. coli 026:B6 x Glutamate Patrizio75
1994 Rat E. coli 055:B5 x MHC I/II Antigen Xu58
1994 Mouse E. coli 0111B4 x O2- generation Chao76
1995 Mouse E. coli 0127:B8 x Cytoskeleton Basset77
1995 Rat E. coli 055 B5 x IL-3 receptor Appel78
1995 Mouse S. abortus equi x ICAM-1 Bell59
1995 Rat E. coli 055:B5 x Gelatinases Gottschall79
1995 Mouse NR x b-chemokines Hayashi80
1995 Rat S. pneumoniae x Toxicity Kim81
1995 Rat E. coli 026:B6 x PGD2,TXB2 Minghetti82
1995 Rat E. coli 026:B6 x cAMP Patrizio83
1995 Mouse E. coli 0127:B8 x Cathepsin B Ryan84
1995 Rat E. coli 055:B5 x Biopterin Sakai85
1995 Mice E. coli (NR) x IL-2 Sawada86
1995 Human E. coli 055:B5 x C1q/C3; TGFb; NOS Walker87
1996 Rat E. coli 055 B5 x CD11b/c & MHC II Buttini54
1996 Mouse S. aureus x Bacterial digestion Fincher88
1996 Mouse NR x IL-12 Lodge89
1996 Mouse NR x Neurons Zhang90
1997 Mouse E. coli 026:B6 x B7 antigen Iglesias91
1998 Rat E. coli 055:B5 x CD54/CD29 Zuckerman92
1998 Rat H. influenzae BBB Permeability Wispelwey53
1998 Rat E. coli 026:B6 x Apoptosis Mayer93
Abbreviations: BBB: blood brain barrier; C: complement; FGF:
fibroblast growth factor; IL: interleukin; MSR: macrophage scavenger
receptor; NOS: nitric oxide synthase; NGF: nerve growth factor; NR:
bacterial species or LPS serotype not specified; TGF: transforming
Table 2: In vitro studies on the mechanism of microglia ROS
production: a historical perspective.
Year Microglia Priming agent Agonist ROS Reference
1986 Rat - PMA O2- Giulian25
1987 Rat - TPA/OZ O2- Colton26
1987 Mouse - TPA/OZ/IgRB O2- Sonderer27
1989 Rat IFN g PMA O2- (+) Woodroofe95
1989 Dog - Antiviral Ab O2- Burge96
1991 Mouse LPS/IFN-g/GM-CSF - O2- Suzumura97
1992 Rat LPS - NO· Boje65
1992 Mouse - PMA O2-,H2O2 Piani98
1992 Mouse IFN-h LPS NO· Chao99
1992 Rat INF a,b,g PMA/OZ O2- (+) Colton100
1992 Rat LPS/IFN-g - NO· Zielasek101
1993 Rat - PMA H2O2 Banati102
1993 Mouse LPS OPZ NO· Corradin103
1994 Rat - PMA/ConA/OZ O2- Klegeris104
1994 Rat - A23187 O2- Colton105
1994 Rat LPS PMA O2- (-) Colton106
1994 Mouse LPS PMA O2- (+) Chao76
1995 Human TNF-a/IFN-g PMA O2- (+) Chao107
1996 Human TNF-a PMA O2- (+) Hu108
1996 Swine IFN-h+ LPS - NO· Hu108
1996 Rat b-amyloid - NO· Ii109
1996 Human IL-1/TNF-a/IFN-g - O2-/NO·(+) Janabi110
1996 Rat - LDL NO· Mohan111
1996 Rat - Myelin O2-/NO· Mosley112
1996 Rat b amyloid PMA O2- (+) Van Muiswinkel113
1996 Rat LPS PMA O2- (+) Van Muiswinkel113
1996 Mouse/Hamster LPS OZ O2-/NO·(-+) Colton114
/Human IL-1 + TNF-a
1997 Rat LPS PMA O2- (+) Mayer52
1997 Rat Albumin PMA O2- (+) Si115
1997 Rat LPS PMA O2-/NO· (-) Si116
1997 Mouse LPS - NO· Murata117
1997 Rat b amyloid OZ/PMA O2- (+) Klegeris118
1997 Human INF-g/IL-1 - NO· Ding119
1998 Rat LPS - NO· Bhat120
1998 Rat LPS - NO· Lockhart121
Abbreviations: Ab: antibody; A23187: calcium ionophore A23187;
ConA: concanavalin A; IFN; interferon; IgRB: antibody-coated red blood
cells; LDL: low density lipoprotein; OZ: opsonized zymosan; PMA:
phorbol myristate acetate; (+) increased production; (-) decreased