Interdependence of hypoxic and innate immune responses.
ABSTRACT Hypoxia-inducible factor (HIF) is an important transcriptional regulator of cell metabolism and the adaptation to cellular stress caused by oxygen deficiency (hypoxia). Phagocytic cells have an essential role in innate immune defence against pathogens and this is a battle that takes place mainly in the hypoxic microenvironments of infected tissues. It has now become clear that HIF promotes the bactericidal activities of phagocytic cells and supports the innate immune functions of dendritic cells, mast cells and epithelial cells. In response to microbial pathogens, HIF expression is upregulated through pathways involving the key immune response regulator nuclear factor-kappaB, highlighting an interdependence of the innate immune and hypoxic responses to infection and tissue damage. In turn, HIF-driven innate immune responses have important consequences for both the pathogen and the host, such that the tissue microenvironment fundamentally influences susceptibility to infectious disease.
- SourceAvailable from: Petra Dersch[Show abstract] [Hide abstract]
ABSTRACT: Deciphering the principles how pathogenic bacteria adapt their metabolism to a specific host microenvironment is critical for understanding bacterial pathogenesis. The enteric pathogenic Yersinia species Yersinia pseudotuberculosis and Yersinia enterocolitica and the causative agent of plague, Yersinia pestis, are able to survive in a large variety of environmental reservoirs (e.g., soil, plants, insects) as well as warm-blooded animals (e.g., rodents, pigs, humans) with a particular preference for lymphatic tissues. In order to manage rapidly changing environmental conditions and interbacterial competition, Yersinia senses the nutritional composition during the course of an infection by special molecular devices, integrates this information and adapts its metabolism accordingly. In addition, nutrient availability has an impact on expression of virulence genes in response to C-sources, demonstrating a tight link between the pathogenicity of yersiniae and utilization of nutrients. Recent studies revealed that global regulatory factors such as the cAMP receptor protein (Crp) and the carbon storage regulator (Csr) system are part of a large network of transcriptional and posttranscriptional control strategies adjusting metabolic changes and virulence in response to temperature, ion and nutrient availability. Gained knowledge about the specific metabolic requirements and the correlation between metabolic and virulence gene expression that enable efficient host colonization led to the identification of new potential antimicrobial targets.Frontiers in Cellular and Infection Microbiology 10/2014; 4:146. · 2.62 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: According to the self-nonself model of immunity, allogeneic T cells are considered as major cause of graft versus host disease (GVHD) following allogeneic stem cell transplantation (SCT). On the other hand, the danger model of immunity suggests that transplant-associated recipient tissue injury rather than donor-derived alloreactive T cells is the main cause of GVHD. What has been less appreciated are the early, both conditioning-dependent and conditioning-independent, events that impair homeostatic cellular adaptations and host-protective immune responses leading to the development of tissue-specific GVHD. The notion of gut injury precipitating in GVHD has been acknowledged by clinicians, with the shift to reduced intensity-conditioning regimens that prevent acute tissue injury and are less disruptive of tissue adaptation to T cell attack. Also, the role of host-protective immune response against pathogens in preventing GVHD has been shown by the lack of severe GVHD in germ free mice as well as an impaired anti-viral immune response during chronic GVHD. This article provides a brief review of the literature on GVHD and suggests that transplant-induced dysregulation of the protective immune response in the recipient of SCT is more important than allogeneic T cells in causing GVHD.Immunological investigations 10/2014; 43(8). · 1.90 Impact Factor
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ABSTRACT: As an essential component of innate immunity, macrophages have multiple functions in both inhibiting or promoting cell proliferation and tissue repair. Diversity and plasticity are hallmarks of macrophages. Classical M1 and alternative M2 activation of macrophages, mirroring the Th1-Th2 polarization of T cells, represent two extremes of a dynamic changing state of macrophage activation. M1-type macrophages release cytokines that inhibit the proliferation of surrounding cells and damage contiguous tissue, and M2-type macrophages release cytokines that promote the proliferation of contiguous cells and tissue repair. M1-M2 polarization of macrophage is a tightly controlled process entailing a set of signaling pathways, transcriptional and posttranscriptional regulatory networks. An imbalance of macrophage M1-M2 polarization is often associated with various diseases or inflammatory conditions. Therefore, identification of the molecules associated with the dynamic changes of macrophage polarization and understanding their interactions is crucial for elucidating the molecular basis of disease progression and designing novel macrophage-mediated therapeutic strategies.Frontiers in Immunology 11/2014; 5:614.
hypoxia and innate
Adapting to low oxygen levels
Rho family Gtpases
Integrating signals for lymphocyte
development and activation
september 2009 volume 9 no. 9
Acute foci of tissue inflammation, whether generated
in response to infection, injury, noxious agents or auto
immunity, present a unique and challenging micro
environment. Hypoxia (low oxygen) or anoxia (complete
lack of oxygen), hypoglycaemia (low blood glucose),
acidosis (high H+ concentration) and abundant free
oxygen radicals are characteristic features of inflamed
tissues, along with the influx of specialized myeloid
cells such as neutrophils and macrophages1,2. In healthy
tissues the oxygen tension is generally 20–70 mm Hg (that
is, 2.5–9% oxygen), whereas markedly lower levels (<1%
oxygen) have been described in wounds and necrotic tis
sue sites3–5. The extreme local hypoxia is a consequence of
decreased perfusion, which is secondary to micro vascular
injury, thrombosis or increased interstitial pressure,
coupled with the metabolic activities of the infectious
pathogen and the recruited inflammatory cells.
Myeloid cells are shortlived cells that are rapidly
mobilized in response to any change in tissue integrity
or entry of pathogenic microorganisms. They carry out
phagocytosis of invading microorganisms and tissue
debris and release a diverse array of antimicrobial mole
cules and proinflammatory mediators. Neutrophils and
macrophages are crucial components of innate immune
defence, serving to localize and eradicate pathogens
and prevent the systemic spread of infection. In par
ticular, neutrophil priming and apoptosis are crucial to
the onset and resolution of granulocytic inflammation.
Deficiencies in the numbers of these specialized phago
cytic cells (for example, following cancer chemotherapy)
or inherited defects in their core effector functions (for
example, in chronic granulomatous disease) greatly
increase susceptibility to recurrent or severe infections.
The intricate regulation of the microbicidal and
inflammatory functions of neutrophils and macrophages
is central to our understanding of mammalian innate
immunity. Innate immune cells must remain quiescent
under normal conditions to avoid unwanted inflamma
tory injury to host tissues, but be capable of instantaneous
activation when recruited to sites of infection. Extensive
investigations have defined cell surface receptors and
downstream signalling pathways that allow these cells
to rapidly activate gene transcription and to release pre
formed antimicrobial effectors following recognition of
pathogens or cytokines. The field is gaining an improved
understanding of how another key feature of the inflam
matory tissue microenvironment, the scarcity of oxygen,
influences the terms of engagement between phagocytic
cells and pathogens. In this Review, we describe how
these front line innate immune effector cells have evolved
to generate energy and carry out their microbicidal func
tions under hypoxic conditions. From these fundamen
tal functions emerges an interdependence of the innate
immune response and the hypoxic response, revealing a
central role for the hypoxiainducible factors (HIFs) as
regulators of mammalian innate defence.
*Department of Pediatrics,
‡Skaggs School of Pharmacy
and Pharmaceutical Sciences,
and §Division of Biological
Sciences, University of
California, San Diego,
9500 Gilman Drive, La Jolla,
California 92093, USA.
Interdependence of hypoxic and
innate immune responses
Victor Nizet*‡ and Randall S. Johnson§
Abstract | Hypoxia-inducible factor (HIF) is an important transcriptional regulator of cell
metabolism and the adaptation to cellular stress caused by oxygen deficiency (hypoxia).
Phagocytic cells have an essential role in innate immune defence against pathogens and
this is a battle that takes place mainly in the hypoxic microenvironments of infected tissues.
It has now become clear that HIF promotes the bactericidal activities of phagocytic cells
and supports the innate immune functions of dendritic cells, mast cells and epithelial
cells. In response to microbial pathogens, HIF expression is upregulated through
pathways involving the key immune response regulator nuclear factor-κB, highlighting
an interdependence of the innate immune and hypoxic responses to infection and tissue
damage. In turn, HIF-driven innate immune responses have important consequences for
both the pathogen and the host, such that the tissue microenvironment fundamentally
influences susceptibility to infectious disease.
Tissue-specific immune responses
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(PHD1, PHD2 and
a O2 abundant: normoxia
Nature Reviews | Immunology
Genes involved in myeloid cell
energy generation, inflammation
b O2 scarce: hypoxia
An important proteolytic
pathway that involves the
tagging of unwanted proteins
with ubiquitin, which allows
their recognition by the
proteasome — a large,
Hif: a central regulator of the hypoxic response
The HIF protein complex was originally discovered
through its contribution to the marked induction
of erythropoietin (EPO) gene transcription under
hypoxic conditions6,7. Further characterization showed
that HIF is a heterodimeric helix–loop–helix tran
scription factor, the expression of which is regulated by
both oxygen and iron (FIG. 1). HIF is active in all mam
malian cells and is now known to regulate the expres
sion of more than 100 genes that function in various
host cellular and systemic responses to stress triggered
by low oxygen levels. HIFcontrolled pathways influ
ence metabolism, angiogenesis, vascular tone, cell
differentiation and apoptosis, and have implications
for normal physiology and development but also for
cancer and many other pathological conditions8,9.
The HIF DNAbinding complex is comprised of the
constitutively expressed HIF1β (also known as ARNT)
subunit, which partners with one of two hypoxia
inducible αsubunits, HIF1α or HIF2α (also known
as EpAs1)7. The HIF αsubunits are unstable under
normoxic conditions as cells continually synthesize
and degrade them. The halflives of HIF1α and HIF2α
are short owing to the activities of a family of oxygen
and irondependent prolyl hydroxylases (pHD1,
pHD2 and pHD3)10, the actions of which direct HIF
αsubunits for degradation by the ubiquitin–proteasome
pathway in a process that depends on interaction with
von Hippel–lindau tumour suppressor protein (vHl)11.
A further level of control is provided by another hydroxy
lase, the asparaginyl hydroxylase factor inhibiting HIF
(FIH; also known as HIF1AN), which has been shown to
Figure 1 | mechanisms of HIF stabilization. a | Under normoxic conditions, hydroxylation of hypoxia-inducible factor 1α
(HIF1α) by prolyl hydroxylases (PHDs) occurs in an O2-dependent manner at amino acid residues 402 and 564. This results
in polyubiquitylation of the HIF1α protein by von Hippel–Lindau tumour suppressor protein (VHL) and ultimately in the
degradation of HIF1α by proteasomes. The asparaginyl hydroxylase factor inhibiting HIF (FIH; also known as HIF1AN)
functions in conjunction with the prolyl hydroxylation, although in this case to hydroxylate an asparagine residue in the
carboxy-terminal domain of HIF1α. This blocks the association of HIF1α with p300–CREB-binding protein (CBP; also
known as CREBBP), which in turn inhibits transcriptional enhancement by the HIF complex (not shown). As all of these
post-translational events depend on intracellular oxygen they are inhibited by oxygen deprivation. b | Under hypoxic
conditions, HIF1A gene expression is upregulated through nuclear factor-κB (NF-κB) activation downstream of Toll-like
receptors (TLRs), and the unmodified form of HIF1α in association with p300–CBP migrates to the nucleus to bind HIF1β
(also known as ARNT), forming a heterodimeric helix–loop–helix transcriptional regulator. The HIF complex binds to target
promoters known as hypoxic-response elements (HREs), leading to the transcription of genes that promote macrophage
and neutrophil energy generation, inflammatory and bactericidal activities, and survival. Ub, ubiquitin.
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© 2009 Macmillan Publishers Limited. All rights reserved
A site-specific recombinase
that recognizes and binds
specific sites known as LoxP.
Two LoxP sites recombine in
the presence of Cre, allowing
DNA that is cloned between
two such sites to be removed
expressed by epithelial cells
and phagocytes that share a
highly conserved ‘cathelin’
12 kDa pro-sequence at the
amino terminus, followed by
diversified mature sequences
at the carboxyl terminus.
Activation of most cathelicidin
precursors requires proteolytic
cleavage to release the
C-terminal domain, which has
inhibit p300–CREbbinding protein (Cbp; also known
as CREbbp)mediated transcriptional coactivation of
the HIFA genes12,13.
under conditions of hypoxia or iron deprivation,
prolyl and asparaginyl hydroxylases are inhibited and
HIF1α or HIF2α can accumulate and translocate to the
nucleus, where they bind HIF1β (FIG. 1). The result
ant heterodimeric HIF complex binds to core penta
nucleotide sequences known as hypoxicresponse
elements (HREs) in the promoter regions of target
genes. Classical HIF target genes include most of the
glycolytic enzymes, glucose transporters, erythropoietin
and the angiogenic factor vascular endothelial growth
factor (vEGF). The HIFregulated genes function
together to decrease mitochondrial oxygen consump
tion14, orchestrate the metabolic shift to anaerobic
glycolysis15 and balance the decreased cellular pH
owing to increased lactic acid production16, thereby
optimizing cell energetics and homeostasis for survival
and function in oxygenpoor environments.
Hif function in myeloid cells
HIF control of myeloid cell inflammatory activities.
Indicative of the central roles of HIF1α in development
and physiology, deletion of HIF1α in mice results in
lethal embryonic defects in vascular development and
morphology17–19. Recently, a conditional gene targeting
strategy exploiting Cre–LoxP recombination was used
for lineagespecific elimination of HIF1α in macro
phages and neutrophils. A mouse line was engineered
to contain LoxP sites flanking the Hif1a gene, and these
mice were then crossed with mice in which the myeloid
cellspecific lysozyme M promoter drives Cre recom-
binase expression. The resultant mice, which showed
markedly decreased HIF1α expression levels specifically
in myeloid cells, have no obvious phenotypic abnormali
ties under normal conditions but showed marked aber
rations in experimental models of acute inflammation20.
In contrast to their wildtype littermates, mice with a
myeloid cell Hif1a conditional deletion did not develop
severe joint swelling and cartilage destruction in a colla
geninduced arthritis model and showed no cutaneous
redness or oedema following application of a chemical
irritant to the skin, indicating impaired inflammatory
responses20. The HIF1αdeficient macrophages and
neutrophils had lower levels of cellular ATp (15–40% of
wildtype levels), highlighting the crucial role of the tran
scription factor for energy generation through glycolysis
in these immune cells20. Evidence of HIF activation in the
diseased tissues of patients with inflammatory dis orders,
such as rheumatoid arthritis21,22, dermato myositis23, neo
natal lupus syndrome24 and atherosclerosis25, suggests
an important role for the hypoxic response in various
HIF control of myeloid cell defence functions.
Neutrophils and macrophages are not only participants
in acute and chronic inflammatory pathologies but also
crucial front line effectors of innate host defence against
invading microbial pathogens. Although the oxygen
percentage in healthy tissues ranges from 2.5–9%
oxygen, markedly lower levels (<1% oxygen) are char
acteristic of wounds and sites of infection (BOX 1). Thus,
phagocytic cells must be adapted to generate energy
and function effectively in oxygendeprived condi
tions, especially as many common bacterial pathogens
proliferate readily in anaerobic microenvironments.
Analysis of the bactericidal capacities of phagocytes
from Hif1a conditional knockout mice confirmed a
pivotal role for the hypoxic response in innate host
defence. Macrophages isolated from mice deficient
in HIF1α are impaired in their capacity to kill Gram
positive and Gramnegative bacteria compared with
wildtype macrophages20,26. when challenged sub
cutaneously with group A strepto coccus, mice with
a myeloid cell Hif1a conditional deletion developed
significantly larger necrotic ulcers and had higher
bacterial loads in the infected tissue and blood26.
Analysis of the host–pathogen encounter by mul
tiple groups has revealed several aspects of myeloid
cell function that depend on HIF. In neutrophils, HIF
induces β2 integrin expression and thereby pro
motes neutrophil binding to the epithelium27. HIF
increases neutrophil expression of antimicrobial
molecules such as cathelicidin peptides and the granule
proteases cathepsin G and elastase26. HIF also extends
the lifespan of functional neutrophils by inhibiting
apoptotic pathways28,29. Increased levels of HIF are
also evident during the differentiation of blood mono
cytes into tissue macrophages30. HIF activity has been
described as a key aspect of phagocytic uptake of
bacteria by macrophages under hypoxic conditions31,
and macrophage production of tumour necrosis
factor (TNF) and synthesis of nitric oxide (No)
through inducible No synthase (iNos) is HIF depend
ent26. HIFresponsive elements are also found in the
genes encoding Tolllike receptors (TlRs), including
TlR2 and TlR6, which are upregulated in response to
hypoxia32. Finally, HIF markedly increases the release
of proinflammatory cytokines and the expression of
costimulatory molecules by murine dendritic cells
(DCs), enhancing their ability to induce allogeneic
lymphocyte proliferation and therefore helping to
bridge innate and adaptive immune responses33.
Box 1 | Defining oxygenation states
Generally defined as either atmospheric oxygen at sea level for tissue culture or as
physiological oxygenation in a well-vascularized and perfused tissue. Oxygenation of
tissues depends on the tissue in question, and in the case of innate immune cells it
becomes an even more elusive quantity to define.
In tissue culture, hypoxia is generally defined as levels that are equivalent to between
0.5% and 3% oxygen by volume in the air that perfuses the growth medium. For actual
tissues in vivo hypoxia is more difficult to define but is generally thought to occur in
any tissue where injury or another alteration in perfusion causes a significant reduction
in tissue oxygen levels relative to those that exist normally. Functionally, hypoxia exists
in vivo whenever oxygen demand exceeds oxygen supply.
Defined in both tissue culture and physiology as the absence of physiologically available
oxygen. Anoxia can occur in tissues in areas of acute infection or severe damage.
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Nature Reviews | Immunology
Initial HIF stabilization
due to decreasing oxygen
HIF transcripts induced
by pathogen encounter
through TLR–NF-κB signalling
IL-1 and IL-12)
one notable exception to the HIFmediated regu
lation of phagocyte function may be the generation of
superoxides by the oxidative burst, which seems to occur
with equal efficiency in wildtype and HIF1αdeficient
Synergism of the hypoxic and innate immune responses.
A surprising consequence of the findings summarized
above is that, because of HIF activation, myeloid cells
phagocytose and kill bacteria better under hypoxic con
ditions than they do under normoxic conditions26,31.
strikingly, bacteria are an even stronger stimulus for HIF
protein stabilization than is hypoxia itself, and bacteria
induced HIF protein stabilization can be readily shown
under normoxia26. Recently, the mechanistic explana
tion for these phenomena has been found to reflect a
close, synergistic relationship between HIF and a central
regulator of innate immunity, nuclear factorκb (NFκb)
(a transcription factor).
NFκb activity is controlled by inhibitor of NFκb
(Iκb) kinases (IKKs), mainly IKKβ, which carry out the
phosphorylationdependent degradation of Iκb inhibitors
in response to infectious or inflammatory stimuli34. HIF
was shown to mediate NFκb activation in neutrophils
under anoxic conditions28 and to promote the expression
of NFκbregulated cytokines in macrophages stimu
lated by lipopolysaccharide (lps) in a TlR4dependent
manner35. Interestingly, hypoxia itself can stimulate
NFκb activation by inhibiting prolyl hydroxylases that
negatively modulate IKKβ catalytic activity36.
NFκb was found to contribute to increased Hif1a
mRNA transcription under hypoxic conditions37,38. The
activation of Hif1a transcription by bacteria or lps
under normoxic as well as hypoxic conditions has been
recently verified in a study using mice deficient in IKKβ39.
Macrophages infected with Grampositive or Gram
negative bacteria, and mice subjected to hypoxia, reveal
a marked defect in HIF1α expression following deletion
of the gene encoding IKKβ39. These results confirm that
transcriptional activation of Hif1a by IKKβresponsive
NFκb is a crucial precursor to posttranscriptional
stabilization and accumulation of HIF1α protein.
because circulating phagocytes have a unique
immune defence function and must transit through dif
ferent microenvironments during rapid mobilization
to infected tissues, the synergistic HIF–NFκb pathway
represents an elegant control mechanism for the special
ized activities of these cells (FIG. 2). phagocyte bactericidal
Figure 2 | HIF regulation of phagocyte innate immune functions. Myeloid-derived phagocytes such as neutrophils and
macrophages have low levels of hypoxia-inducible factor (HIF) under normal conditions as they circulate in the oxygen-rich blood.
When recruited to tissue sites of infection, they migrate across the endothelium and immediately encounter a decreasing oxygen
gradient, which leads to decreased prolyl hydroxylase activity and increased stabilization of HIF1α protein. HIF1α translocates to
the nucleus and forms a functional heterodimeric transcription factor with HIF1β (also known as ARNT) (not shown). Expression of
innate immune response genes that contain hypoxic-response elements (HREs) in their promoters is increased, but maximal
activation occurs only through Toll-like receptors (TLRs) and nuclear factor-κB (NF-κB) activation following pathogen encounter,
which functions to boost HIF1A transcription. HIF activity promotes phagocytosis; inhibits apoptosis to increase phagocyte
lifespan; stimulates the release of antimicrobial peptides, granule proteases, vascular endothelial growth factor (VEGF, which
increases vascular permeability) and pro-inflammatory cytokines (such as tumour necrosis factor (TNF), interleukin 1 (IL-1) and
IL-12); upregulates TLR expression; and activates the production of nitric oxide by inducible nitric oxide synthase.
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An injury in which the tissue
first suffers from hypoxia as a
result of severely decreased, or
completely arrested, blood
flow. Restoration of normal
blood flow then triggers
exacerbates the tissue
and proinflammatory capacities can be maintained
in an ‘off’ state while the myeloid cells circulate in the
oxygenrich blood, but can then be activated in response
to the decreasing oxygen gradient that is encountered
following endothelial transcytosis and entry into the
infected tissues. The primed phagocyte then undergoes
a more potent stimulation of the HIF pathway on direct
pathogen encounter and, through recognition of path
ogenassociated molecular patterns by TlRs, activation
of NFκb and upregulation of Hif1a mRNA. The maxi
mal ‘on state’ of bactericidal capacities is enhanced by
the release of proinflammatory cytokines and upregu
lation of TlR expression. This elegant control system
links HIF to the myeloid cell response, ensuring that
proinflammatory mediators, degradative enzymes and
antimicrobial peptides are expressed preferentially at
sites of infection, but not in healthy tissues where they
would cause unwanted damage to host cells.
so far, functional studies of the HIF–NFκb pathway
in myeloid cell innate immune functions have centred
on the role of the HIF1α subunit, but it will be important
to expand these analyses to investigate the potential syn
ergistic or modulatory roles of the HIF2α subunit in this
context. periods of prolonged exposure to hypoxic con
ditions (18 hours) affect the expression of many macro
phage cytokines and receptors, including interleukin1β
(Il1β), Il8, vEGF, angiopoietin and CXCchemokine
receptor 4 (CXCR4) in both mouse and human mac
rophages. In addition, recent studies using RNA inter
ference and pharmacological inhibitors suggest that
HIF1α and HIF2α, more so than NFκb, are important
in orchestrating the changes in macrophage receptor and
cytokine gene expression40. Additional evidence suggests
that HIF1α, but not HIF2α, underpins the synergistic
induction of iNos expression and other HREdependent
transcriptional activities in macrophages following
exposure to lps and hypoxia41.
role of Hif in other cell types
Evidence is mounting showing that HIF is a key regula
tor of the intrinsic immune and inflammatory responses
in various nonmyeloid cell types, including tissue
epithelial cells and other specialized leukocytes. For
example, the skin provides a highly effective physical,
cellular and chemical barrier against microbial penetra
tion42. In response to bacterial pathogens, keratinocytes
produce peptides of the cathelicidin and βdefensin
family that can directly kill microbial pathogens43. HIF
is expressed at high levels in the skin, which is a hypoxic
organ even in noninflammatory settings44. Following
targeted deletion of Hif1a in keratinocytes, mice show a
defect in controlling necrotic skin infection by group A
streptococci44. specific RNA interference studies con
firmed that HIF1αmediated regulation of keratinocyte
cathelicidin production is crucial for cutaneous defence
against infection with this invasive pathogen44.
HIF expression is upregulated in the gut epithelium dur
ing ischaemia–reperfusion injury, and the level of HIF acti
vation during the reperfusion phase is strongly increased
by exposure to lps or the bacterium Pseudomonas aeru‑
ginosa45. Targeted manipulation of HIF1α expression
in colonic epithelium also suggests potential roles for
HIF1α in the regulation of intestinal mucosal inflamma
tory responses, although the directionality of the effects
has been conflicting. In one study46, mice with intestine
specific disruption of HIF1α expression were protected
against dextran sulphate sodiuminduced colitis, whereas
those with constitutive HIF expression (as a result of vHl
deletion) had increased expression of proinflammatory
mediators, including macrophage migration inhibitory
factor (MIF), leading to markedly increased oedema and
cellular infiltrates. However, several other studies using
different mouse colitis models indicated the opposite:
a protective effect of HIF against colonic inflammation
following genetic manipulation47 or pharmacological
Mast cells are specialized granulocytic cells that are
resident in the skin and the mucosa of the respiratory
and gastrointestinal tracts. Their roles in allergy are well
studied and they are increasingly recognized to func
tion in both innate and adaptive immune responses50.
Activation of HIF in human mast cells leads to release
of proinflammatory cytokines such as Il8 and TNF51.
HIF activation in mast cells of the bronchial epithe
lium stimulates vEGF expression, leading to increased
vascular permeability, protein extravasation into the
alveolar space and airway oedema52. Moreover, HIF
activation stimulates histidine decarboxylase expres
sion by human mast cells, catalysing the formation of
histamine, a potent inflammatory mediator53. To date,
the role of HIF in eosinophil inflammatory functions
has not been examined directly.
Hif inflammatory responses during sepsis
sepsis, the leading cause of death in intensive care units,
is an aberrant and potentially lethal host response to
overwhelming infection, in which bacteria or lps pro
voke uncontrolled release of proinflammatory cytokines
from immune cells, including monocytes and macro
phages. lps raises HIF levels in macrophages through
activities of the mitogenactivated protein kinase
(MApK) and NFκb signal transduction pathways37,39,
leading to increased levels of Hif1a mRNA transcripts,
which are accompanied by a TlR4dependent decrease
in the levels of mRNAs encoding prolyl hydroxylases35.
studies of lps challenge of mice with HIF1αdeficient
myeloid cells identified HIF as a crucial determinant of
the sepsis phenotype, promoting highlevel release of the
proinflammatory cytokines TNF, Il1 and Il‑12. As a
consequence, Hif1a deletion in the macrophage lineage
protects animals against lpsinduced mortality and
blocks the clinical manifestations of sepsis, including
hypotension, tachycardia and hypothermia35.
HIF transcriptional regulation also modulates pro
inflammatory cytokine production by CD4+ and CD8+
T cells but, in contrast to findings in myeloid cells, epithe
lial cells and mast cells, the net effect of T cellproduced
HIF might be inhibitory. For example, following T cell
receptor activation, the release of TNF and interferonγ
(IFNγ) by T cells with targeted deletion of Hif1a was
higher than release by wildtype T cells54. The activated
HIFdeficient T cells showed enhanced proliferation
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Caecal ligation and
An experimental model of
peritonitis in rodents, in which
the caecum is ligated and then
punctured. This leads to
leakage of intestinal bacteria
into the peritoneal cavity and
and contributed to blocking bacterial proliferation in a
caecal ligation and puncture model of sepsis55. The para
doxical behaviour of HIF in activated T cells may derive
from alternative splicing and expression of an isoform
of HIF1α that inhibits cellular activation in a delayed
feedback manner56. Data from studies involving the
deletion of Hif1a specifically in T cells indicate that tight
regulation of HIF function in these cells is crucial to pre
vent cell death, and imply that T cells may have a minor
role in hypoxic tissues owing to hypoxiamediated and
HIFdependent cell death57.
Hif dynamics in response to infectious pathogens
Viruses. Acute infection with viruses is generally found
to induce HIF protein stabilization in target cells (TABLE1),
thus provoking local inflammation. For example, the
common respiratory syncytial virus (Rsv) induces HIF
expression by human bronchial epithelial cells through
a Nodependent pathway, stimulating vEGF produc
tion and the airway oedema that is characteristic of
acute Rsv infection58. In some cases, the HIFdependent
innate immune response to viral infection may help to
mitigate cytolytic injury and viral replication. vesicular
stomatitis virus (vsv) infection is an acute illness
resulting in mouth ulcers in cattle and occasionally
in humans. HIF activation by hypoxia or pharmaco
logical agents can increase the expression of IFNβ and
other antiviral genes and promote cellular resistance
to vsv infection59.
by contrast, with certain persistent viral infections
the induction of HIF fails to result in eradication of the
virus. An unfortunate consequence of HIF activation
in these circumstances is that increased vEGF and the
accompanying proangiogenic programme can con
tribute to oncogenic transformation. This seems to
be the case in chronic infections with the hepatitis b
and C viruses (Hbv and HCv), which are epidemio
logically associated with the development of hepato
cellular carcinoma, a highly vascularized solid tumour.
Experimental evidence of this includes the finding that
HIF levels are increased in liver cells transfected with
the oncogenic X protein of Hbv (Hbx) and in the livers
of Hbxtransgenic mice60. Hbx interacts directly with
HIF1α to block its association with vHl and degrada
tion by the ubiquitin–proteasome pathway61. Recently,
HCv infection has also been found to stabilize HIF1α
protein, with the involvement of the NFκb and MApK
signalling pathways, stimulating vEGF production and
Human papilloma virus type 16 (Hpv16) is an
aetiological agent of cervical interstitial neoplasia
that, if untreated, can progress to cervical carcinoma.
Transfection of human cervical cells with the Hpv16
oncoproteins E6 and E7 induces vEGF expression and
capillary formation in a HIFdependent manner63,
and Hpv16 and HIF1α act synergistically to promote
cancer lesions when expressed transgenically in the
cervical epithelium of mice64. Increased HIF levels
Table 1 | effects of infectious pathogens on Hif levels and contribution to disease pathogenesis
PathogenEffect on HIF
Effect of altered HIF on disease pathogenesisRefs
Streptococcus pyogenesIncreasesActivation of phagocyte killing35
Streptococcus agalactiaeIncreasesActivation of phagocyte killing20
Pseudomonas aeruginosa IncreasesActivation of phagocyte killing35
Salmonella typhimurium IncreasesActivation of phagocyte killing71
Bartonella henselaeIncreasesAngiogenesis and vascular lesions 73
DecreasesPromotes intracellular survival of bacterium 74
IncreasesPhagocyte activation, but with high systemic doses,
cytokine storm and sepsis syndrome occur
Respiratory syncytial virus
IncreasesActivation of mucosal defences 72
Increases VEGF release and airway oedema58
Vesicular stomatitis virusIncreasesType I interferon production and cellular resistance to virus59
Hepatitis B virusIncreases Neovascularization and oncogenesis60
Hepatitis C virusIncreasesNeovascularization and oncogenesis62
Human papilloma virusIncreases Neovascularization and oncogenesis63,64
Human herpesvirus 8
IncreasesReactivation of virus from latency69,70
Increases Preserves viability of infected host cell75
Leishmania amazonensis IncreasesDevelopment of skin ulcers77
HIF, hypoxia-inducible factor; VEGF, vascular endothelial growth factor.
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© 2009 Macmillan Publishers Limited. All rights reserved
compounds that are secreted
by numerous types of bacteria
and that have a high affinity for
iron and other metal ions.
These molecules chelate metal
ions and carry them into the
cell through specific receptors,
promoting bacterial survival in
Microsatellites such as the
SLC11A1 (GT/CA)n dinucleotide
repeat tend to form Z-DNA, an
unstable left-handed form of
DNA that is transiently induced
during gene transcription by a
moving RNA polymerase and
stabilized by negative
supercoiling. Polymorphisms in
such microsatellites can
activate or repress gene
transcription in a
are correlated with poor prognosis of patients with
advanced cervical cancer lesions, many of which are
demonstrably hypoxic65. HIF activation is also appar
ent during chronic infection with other viruses that are
associated with the risk of neoplastic transformation,
including human T cell leukaemia virus type I66 and
Crosstalk between viral genes and HIF activation has
recently been shown to have an intriguing role in regu
lating the latency and reactivation of human herpes
virus 8 (HHv8). HHv8 infection is associated with
the endothelial tumour Kaposi’s sarcoma in patients
with AIDs. biopsies of Kaposi’s sarcoma lesions show
high levels of HIF, and HHv8 infection of endothelial
cells can stabilize HIF1α subunits and increase HIF
target gene expression69. The HHv8 latencyassociated
nuclear antigen stimulates Hif1a mRNA transcription
and also physically interacts with the HIF heterodimer
to enhance its promoterbinding activities70. Induction
and coactivation during HHv8 infection allow HIF to
bind HREs in the viral genome itself; these include one
in the promoter of the gene encoding Rta, a key protein
involved in reactivation of the virus from latency to a
lytic replication phase70.
Bacteria. Increased levels of HIF are observed in
macro phages and neutrophils stimulated by various
bacterial species, including group A and b strepto
cocci, Staphylococcus aureus, Salmonella typhimurium
and P. aeruginosa20,26,35,71, indicating that HIF responds
in a general manner to bacterial infection (TABLE1).
The myeloid cell HIF response pathway is beneficial
to innate immune defence, promoting bacterial kill
ing in vitro20,26,35 and restricting the spread of infection
in vivo26. bacterial products such as lps and peptido
glycan can activate TlRs and NFκb signalling to
increase the transcription of Hif1a37. posttranslational
HIF1α protein stabilization is provided by the exhaus
tion of oxygen at the tissue site of infection and, perhaps
in certain cases, through iron sequestration by bacte
rial siderophores. Indeed, siderophoredeficient Yersinia
enterocolitica fails to induce HIF activation in intestinal
peyer’s patches72 and the virulence of Y. enterocolitica
is increased in mice that lack intestinal HIF1α expres
sion, suggesting that the HIF response is important for
mucosal innate defence.
Bartonella henselae is a facultative intracellular
bacterium that causes an angioproliferative disorder
known as bacillary angiomatosis in immunocompro
mised patients. bacillary angiomatosis lesions show
high levels of HIF expression, and B. henselae activa
tion of HIFinduced vEGF release is likely to provoke
a proangiogenic programme that contributes to the
characteristic tissue pathology73. Another intracellular
bacterial pathogen, Chlamydia pneumoniae, has evolved
a mechanism to counteract HIF protein stabilization,
thereby inhibiting innate immune activation and pro
moting its survival in host cells. secretion of a chlamy
dial proteaselike activity factor into the cytoplasm
degrades accumulated HIF1α, facilitating continued
C. pneumoniae replication during hypoxia74.
Parasites. Toxoplasma gondii is an obligate intracel
lular parasite that produces opportunistic infections
in fetuses and in immunocompromised individuals. It
rapidly induces HIF expression by infected fibroblasts75,
which leads to upregulation of genes encoding glyco
lytic enzymes, glucose transporters and vEGF76. under
hypoxic conditions in the tissues (brain, muscle and ret
ina) in which the parasite produces serious clinical pathol
ogy, T. gondii replication and organelle maintenance were
severely impaired in host cells that lacked HIF1α. It is
thought that T. gondii has evolved to induce HIF expres
sion because a particular HIF target gene is essential to
parasite growth or because HIF activation is necessary
to preserve the health of the host cell in which the para
site has become established75. Cutaneous lesions can be
generated in bAlb/c mice by infection with Leishmania
amazonensis, and in the later stages of infection HIF is
induced in the cytoplasm and parasitophorous vacuoles
of macrophages recruited to the skin lesions77. whether
this observed HIF induction contributes to immune
resolution of leishmanial infection is not yet understood.
HIF and SLC11A1 allele expression phenotypes. solute
carrier family 11, member A1 (slC11A1; also known as
NRAMp1) is a protoncoupled divalent ion transporter
that is involved in iron metabolism, resistance to patho
gens and inflammatory responses. SLC11A1 was the first
infectious disease susceptibility gene to be identified by
positional cloning, and allelic variation in SLC11A1 alters
the risk for development of leishmaniasis78 and tubercu
losis79 as well as autoimmune conditions such as juvenile
rheumatoid arthritis80 and type 1 diabetes81. Interestingly,
HIF differentially binds and activates Z-DNA-forming micro-
satellite polymorphisms in the SLC11A1 promoter region,
thereby shaping allele expression phenotypes71, a newly
described function for a transcription factor. Through its
differential interaction with variant SLC11A1 promoters,
HIF transcriptional regulation has the potential to influence
heritable differences in infectious and inflammatory disease
susceptibility within and between human populations71.
Hif: a drug target to boost innate immunity
Given the accumulating evidence that HIF functions
as a ‘master regulator’ of the innate immune function
of phagocytes82, it is possible that boosting HIF activity
through pharmacological strategies might provide a new
approach to aid the treatment of certain infectious disease
conditions83. This concept is supported by the observa
tion that macrophages that lack vHl and thus have con
stitutively high levels of HIF are markedly more efficient
than wildtype macrophages at killing Grampositive and
Gramnegative bacteria in vitro26. This implies that normal
phagocytic cells are not as adept at killing bacteria as they
could be, mainly because their activation is tightly regu
lated to limit unnecessary inflammatory injury. However,
the common clinical scenario of invasive bacterial infec
tion is linked to a failure of innate immunity to control the
infecting pathogen, and it is possible that such patients
might benefit from augmentation of phagocytic cell bacte
ricidal activity by HIF. As proofofprinciple, addition of a
series of pharmacological agonists of HIF, each a ‘hypoxia
NATuRE REvIEws | Immunology
voluME 9 | sEpTEMbER 2009 | 615
© 2009 Macmillan Publishers Limited. All rights reserved
mimetic’ that restricts prolyl hydroxylase access to iron,
directly enhanced mouse macrophage bactericidal activity
in vitro26. similarly, a dosedependent enhancement of the
bactericidal activities of human whole blood, neutrophils
and the macrophage cell line u937 against the pathogen
S. aureus was achieved using one such hypoxia mimetic,
lmimosine84. local treatment with lmimosine sig
nificantly delayed progression of S. aureus abscesses in a
mouse subcutaneous challenge model84.
HIF agonists that are designed to activate phagocyte
bactericidal mechanisms could conceivably be used
alongside conventional antibiotics in localized infections,
and would be predicted to function effectively against
drugresistant bacteria such as methicillinresistant
S. aureus (MRsA). The selective pressure for pathogens
to evolve resistance to HIF agonist therapy may be neg
ligible as the drug targets the host and not the pathogen,
thereby deploying a multifaceted combination therapy
of natural antimicrobial molecules85. The effects of such
drugs would not be restricted to immune cells. However,
chronic administration of a prolyl hydroxylase inhibitor
or HIF agonist to nonhuman primates was not associ
ated with significant toxicity, and these compounds have
advanced to phase Ib–II clinical trials in over 700 patients
for treatment of the anaemia associated with chronic kid
ney disease86. An important cautionary note should be
emphasized: based on evidence from studies of mice35,
HIF agonists are probably inappropriate for systemic
therapy of patients that have disseminated infections and
symptoms of sepsis, as macrophage proinflammatory
cytokine and No release could be rapidly increased and
symptoms could worsen. Instead, one appealing starting
point may be local or topical administration for treatment
or prophylaxis of bacterial skin and wound infections,
where fortification of the antimicrobial barrier provided
by keratinocytes and myeloid cells could be coupled with
the reported enhancement of cutaneous wound healing
associated with HIF augmentation87.
Finally, it is possible that strategies to inhibit HIF for
the treatment of chronic inflammatory disorders, such
as rheumatoid arthritis, may provide a safer therapeutic
margin than cytotoxic agents and highdose steroids,
as posttranslational regulation of HIF1α levels may
allow rapid restoration of innate immune function
of phagocytes following drug withdrawal in the event of
conclusions and future directions
A wealth of emerging information shows that HIF and the
hypoxic response are deeply involved with the regulatory
pathways of innate immune defence. The key implica
tion of these findings is that the nature and magnitude of
host bactericidal and inflammatory activities are highly
dependent on factors in the local tissue microenviron
ment — for example, oxygen tension and iron availability
— and cannot be simply extrapolated from in vitro model
systems under ambient conditions. Through HIF control
of immune cell energetics and gene expression pathways,
antimicrobial activities can be focused and amplified
where they are needed most, namely foci of tissue infec
tion, which are harsh and threatening microenvironments
where oxygen and nutrients are limiting and cytotoxic
molecules abound. we anticipate that future studies
will reveal that important human pathogens modulate
HIF activation pathways to subvert innate immunity or
provoke dysregulated inflammation, contributing to key
clinical manifestations. A detailed understanding of the
relationships between HIF, pathways of innate immune
signal transduction such as TlR–NFκb signalling and
the deployment of various immune effector molecules will
provide a clearer and more physiological understanding
of infectious and inflammatory disease pathogenesis.
because of the short halflife and wellunderstood mecha
nism for posttranslational regulation of HIF levels, HIF is
an attractive pharmacological target to finetune immune
cell functions for the treatment of human disease.
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erythrocytosis, and modest fetal hemoglobin expression
in rhesus macaques. Blood 110, 2140–2147 (2007).
87. Botusan, I. R. et al. stabilization of HIF‑1α is critical to
improve wound healing in diabetic mice. Proc. Natl
Acad. Sci. USA 105, 19426–19431 (2008).
The authors’ studies in the area of HIF and innate immunity
have been supported by Us National Institutes of Health
grant AI060840 and the American Asthma Foundation.
angiopoietin | CXCR4 | FIH | HIF1α | HIF1β | HIF2α | IFNγ |
IL-1β | IL-8 | iNOS | MIF | SLC11A1 | TNF | VEGF
Randall S. Johnson’s homepage:
Victor Nizet’s homepage: http://nizetlab.ucsd.edu
All lInks ARE ActIvE In tHE onlInE PdF
NATuRE REvIEws | Immunology
voluME 9 | sEpTEMbER 2009 | 617
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