Available online at www.sciencedirect.

com

Oestrogen and immunomodulation: new mechanisms that impact

on peripheral and central immunity
Suchita Nadkarni and Simon McArthur
The regulation of the immune response to infection or tissue
damage is a complex interplay of multiple factors, but it has
long been recognised that steroid hormones can exert powerful
modulatory effects at all levels of the innate and adaptive
immune systems. Although most attention has been paid to
glucocorticoids given their widespread clinical use, it is
becoming increasingly clear that sex steroid hormones, and in
particular the principle female sex steroid oestrogen, exerts
potent effects upon the immune response. In this review, we
will discuss the latest findings on the impact of oestrogen upon
various cellular components of the immune system, and how
this hormone can offer new opportunities to pharmacologically
harness the immune response.
Addresses
Department of Biochemical Pharmacology, William Harvey Research
Institute, Barts and the London School of Medicine, Charterhouse
Square, London EC1M 6BQ, UK
Corresponding authors: Nadkarni, Suchita (s.nadkarni@qmul.ac.uk) and
McArthur, Simon (s.mcarthur@qmul.ac.uk)

Current Opinion in Pharmacology 2013, 13:576581

This review comes from a themed issue on Immunomodulation
Edited by Catherine Godson and Mauro Perretti
For a complete overview see the Issue and the Editorial
Available online 31st May 2013
1471-4892/$ see front matter, # 2013 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.coph.2013.05.007

Innate immunity
Following exposure to infection or tissue damage, there is
a rapid mobilisation and extravasation of neutrophils,
effectively serving as the first arm of the immune
response. Excessive or inappropriate neutrophil accumulation, or a failure in their removal by macrophages, can
induce significant damage to otherwise healthy tissue,
which can lead to both acute and chronic inflammatory
diseases. Restricting neutrophil recruitment is therefore
one of the most important ways in which oestrogen can
regulate the immune response in humans [1], as well as a
wide variety of acute [2,3] and chronic [4,5] animal
inflammatory models. A number of recent studies have
focused on the role of oestrogen in the regulation of
neutrophil recruitment, by two principle mechanisms
of action: namely the control of neutrophil chemotaxis
and the modulation of neutrophilendothelial cell interactions.
Current Opinion in Pharmacology 2013, 13:576581

Oestrogen has been shown to decrease production of the

major neutrophil chemoattractants CXCL1, CXCL2 and
CXCL3 at inflammatory sites in rodent models of intestinal [4,6], lung [3,5,6] and vascular [7] injury, an action
which directly led to decreased neutrophil accumulation.
Similarly, oestradiol has been shown to limit release of the
potent neutrophil chemoattractant CXCL8 from human
monocytes ex vivo [8]. The recruitment and extravasation
of neutrophils not only requires exposure to chemoattractant agents but also involves a series of critical interactions between neutrophils themselves and endothelial
cells. Oestrogen, or its mimetics such as resveratrol, have
recently been shown to limit adhesion of both human and
rodent neutrophils to activated endothelial cell monolayers under shear stress conditions in vitro [911] and to
vascular endothelial cells in vivo [9], directly limiting
neutrophil transmigration and tissue infiltration. Our
own studies have confirmed that this action of oestrogen
is mediated through the rapid upregulation of the wellknown anti-inflammatory protein annexin A1 on neutrophils, and that removal of this protein by either immunoneutralisation or genetic deletion abated the regulatory
effects of oestrogen upon neutrophil extravasation both in
vitro and in vivo [9], see Figure 1.
Further studies have extended the idea that oestrogen
can directly influence neutrophil activation, with both
human and rodent cells having been shown to respond to
the hormone through a reduction in oxidative metabolism
[12], a feature of potentially great importance, given that
excessive oxidative damage is the principal mechanism
whereby over-exuberant neutrophil accumulation can
injure healthy tissues. These studies support by our
recent work showing oestrogen induces a distinct
CD62Llow/anti-inflammatory neutrophil phenotype [9].
The vast majority of extravasated cells undergo apoptosis
in situ. Removal of these effete cells by monocytes and
macrophages is of critical importance for inflammatory
resolution, as apoptotic cells can rapidly progress into
secondary necrosis and become potent sources of inflammation in their own right. Phagocytic clearance of apoptotic neutrophils aids resolution not only through the
removal of potential pro-inflammatory stimuli, but
through the induction of an alternatively activated
phenotype in the phagocyte itself, accompanied by the
induction of cytokines such as IL-10 and TGFb [13].
Mice specifically lacking oestrogen receptor alpha (ERa)
expression in cells of the myeloid lineage [14!] showed
both a defect in inflammatory cell clearance by
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Oestrogen and immunity Nadkarni and McArthur 577

Figure 1

Neutrophil

Oestrogen induces
externalisation of Annexin A1
to the surface of the
neutrophil

Oestrogen binds to its receptor

TNF
IL-1
IL-6

CXCL1,2 3

Oestrogen
NFB

Annexin A1 inhibits
neutrophil adhesion to the
endothelial cell, preventing
potentially harmful
inflammation

IB

Target Tissue

Current Opinion in Pharmacology

Oestrogen and the neutrophil. This figure focuses on the direct effects of oestrogen upon the neutrophil, and how oestrogen can influence neutrophil
chemoattraction through actions in target tissues. In particular, the relative roles of NFkB and annexin A1 are highlighted.

macrophages, and a failure in macrophage phenotypic

conversion from classically to alternatively activated
forms. A further study revealed that oestrogen limits the
numbers of classical macrophages in atherosclerotic lesions
in monkeys fed a high cholesterol diet [15], together
suggesting an important endogenous role for oestrogen.
Oestrogen has been shown to markedly attenuate the
release of pro-inflammatory mediators such as TNFa,
IL-1b and IL-6 from both neutrophils and macrophages
in rats [16], mice [17] and humans [18!!]. Intriguingly, a
number of recent studies have identified the inhibition of
NFkB signalling by oestrogen as lying at the heart of both
these actions and in the reduction of chemokine release
from injured tissues. Oestrogen has been shown to both
enhance production [7] and limit degradation following
phosphorylation of the endogenous NFkB inhibitor
IkBa [18!!], acting via regulation of the microRNAs
let-7a and miR-125b [18!!]. Together, these actions limit
levels of NFkB nuclear translocation and hence prevent
the transcription of pro-inflammatory cytokine and chemokine genes.
www.sciencedirect.com

Together, these studies have revealed a number of

important ways through which oestrogen can regulate
the innate immune response, whether by modulation
of cytokine and chemokine production through interactions with NFkB signalling, or by direct induction of
pro-resolution phenotypes in neutrophils and macrophages through annexin A1 or ERa respectively. We
suggest that these identified mechanisms highlight the
important role of oestrogen in innate immunity, and make
a compelling case for further study of the regulatory roles
the hormone plays in the response to injury and infection.

Adaptive immunity
Balance in the immune system is tightly regulated by
concerted interactions between the professional antigen
presenting cells, dendritic cells (DCs), and T and B
lymphocytes. Dysregulation of this tolerant state can lead
to a variety of pathologies including the failure to recognise self-antigens appropriately, leading to autoimmune
diseases. Oestrogens association with the adaptive
immune system is evident through its ability to modulate
a variety of immune responses and expression of its
Current Opinion in Pharmacology 2013, 13:576581

578 Immunomodulation

receptors, ERa and ERb on T and B cells, as well as DCs

[19,20], suggesting that this hormone can regulate their
responses.
Autoimmune diseases such as rheumatoid arthritis (RA),
multiple sclerosis (MS) and systemic lupus erythematosus (SLE), can be used to highlight the distinct role
oestrogens can play on cells of the adaptive immune
system. For example, women who suffer from MS and
RA can undergo remission during pregnancy at a time
when oestrogen levels are high, but experience disease
relapse post-partum [21,22]. On the other hand, women
who suffer from SLE experience cyclical changes in their
disease during the menstrual cycle, with a worsening of
symptoms correlating with high oestrogen levels during
the cycle [23]. This differential role of oestrogen in
autoimmune diseases could be dependent on whether
the disease is B-cell mediated (such as SLE) or T cell
mediated (such as RA and MS).
Oestrogens detrimental role in SLE may be due to the
appearance of auto-antibodies against ERa; auto-antibodies targeting this receptor are capable of interfering
with T cell homeostasis, promoting their apoptosis [24].
Furthermore, oestrogen has been shown to increase antiDNA antibodies and maintain B cell survival and activation via the up-regulation of CD22 and SHP-1, resulting in decreased signalling through the B cell receptor and
subsequent induction of auto-reactive B cells [25].
Further studies have added to these findings, suggesting
the oestrogen is responsible for promoting systemic
inflammation through the induction of B cell activating
factor (BAFF) and interferon-inducible genes [26]. SLE
patients experience augmented serum levels of the type-I
interferon, IFNa, as well as over-expression of IFNarelated genes [27]. Plasmacytoid DCs (pDC) are a subset
of DC that respond to viral infections and produce IFNa
via the toll-like receptors TLR-7 and TLR-9. A recent
study has shown that oestrogen, via ERa, is capable of
promoting TLR-7/9-induced IFNa release, suggesting a
potential mechanism as to why oestrogen could be
adverse in SLE [28].
Contrary to its pathogenic effects on B cells in SLE,
oestrogen can induce a protective state in B cells in the
mouse model of multiple sclerosis, experimental autoimmune encephalitis (EAE). Administration of oestrogen
to EAE mice depleted of protective regulatory T cells
(Tregs, see below) can still induce a protective response.
Here, the authors suggest that in the absence of Tregs,
compensatory pathways are activated, resulting in the
augmentation of oestrogen-induced regulatory B cells,
with enhanced secretion of the anti-inflammatory cytokine, IL-10 [29].
DCs are professional antigen presenting cells (APC),
meaning that they are capable of processing antigen
Current Opinion in Pharmacology 2013, 13:576581

and presenting them to T cells, a process that instigates

the immune response. For this reason, DCs are often
described as bridging the gap between the innate and
adaptive immune system. The efficient presentation of
antigen relies on expression of MHC II. A recent paper
has demonstrated that oestrogen, via ERa, is capable of
promoting DC differentiation and MHC II expression, by
upregulating the transcription factor, IRF4 [30]. Oestrogen also promotes a tolerogenic phenotype in DC [31!!]
by upregulating the necessary markers for antigen presentation, as well as inhibitory molecules such as the
programme cell-death ligands, PD-L1 and PD-L2.
Additionally, oestrogen is capable of promoting the
release of the regulatory cytokines, IL-10 and TGFb,
while attenuating the release of IL-12 and ameliorating
EAE [31!!].
Tregs are a subset of T cells capable of inducing immune
tolerance, by dampening down pro-inflammatory
responses (reviewed elsewhere [32]). The role of oestrogen in immune tolerance has been further characterised
in pregnancy, where foetalmaternal tolerance is
mediated by Tregs, with an enrichment of Tregs at the
foetalmaternal interface [33]. Aberrations in the number
of Tregs and their suppressive capacity can lead to
pregnancy complications including pre-eclampsia [34]
and spontaneous abortion [35]. Oestrogen is capable of
inducing Tregs in vitro and promoting their proliferation
via the PI3K/AKT signalling pathway with a concomitant
augmentation in their suppressive capacity [36], and of
mediating Treg suppression by promoting perforin-dependent killing of effector cells [37].
Oestrogens ability to maintain immune tolerance is not
just dependent on the induction of Tregs, and its effects
have broader implications on other T cell subtypes. For
example, oestrogen has been shown to inhibit pro-inflammatory Th1 and Th17 cytokines, including IFNg, TNFa
and IL-17, in EAE, acting specifically via ERa [38!]. In
addition to inhibiting pathogenic T cells, oestrogen has
been found to limit the migration of pathogenic T cells to
the central nervous system in EAE. However, the authors
of these findings suggest that oestrogen does not directly
modulate chemokine expression on the T cell, but rather
modulates adhesion molecule expression on the endothelium, which in turn can influence T cell migration [39].
Taken together, these recent studies highlight diseasespecific actions of oestrogen within the adaptive immune
response.

Central immunity
It is a little recognised fact, but both male and female
brains are steroidogenic organs associated with a basal
production of oestrogen and that, more importantly, localised upregulation of oestrogen synthesis is one of the first
responses to brain injury [40]. Whilst many studies have
investigated a role for oestrogen as a neuroprotective
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Oestrogen and immunity Nadkarni and McArthur 579

agent in neurodegenerative disease [41], fewer have

directly considered its role as a regulator of the immune
cells of the brain, the microglia and astrocytes, and their
actions in neuroinflammatory disease. Several recent studies have, however, suggested that oestrogen may suppress inflammatory cytokine and chemokine gene activity
within the rodent brain under basal conditions or following traumatic injury [42,43], indicating a potential action
of the hormone upon inflammatory glia.

Whilst astrocytes are not developmentally related to

myeloid or lymphoid cells, they play an important role
in central nervous system immunity, and are fully capable
of producing and responding to inflammatory mediators.
Multiple studies have shown, moreover, that astrocytes
are potently regulated by oestrogen with the steroid
inhibiting cytokine and chemokine production in response
to both viral [44] and bacterial [45] challenge. Additionally,
astrocyte-specific deletion of ERa prevented the protective

Figure 2

Inhibit
neutrophilendothelium
interactions

Reduce
oxidative
metabolism

Promote IFN
release in SLE

Decrease neutrophil
chemoattractants
Induction of
tolerogenic DC

CH3

OH

Oestrogen

HO
Inhibition of Th1 and
Th17 cells
Maintenance of
B cell survival
in SLE
Induction of
regulatory T
cells in vitro

Enhance
apoptotic cell
clearance

Promote
macrophage
alternative
activation

Induction of
regulatory B
cells in EAE

Current Opinion in Pharmacology

Oestrogen and the immune system. This figure summarises how oestrogen can influence the phenotype and behaviour of cells of the innate and
adaptive immune system, modulating the activity of virtually every cell type involved.
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Current Opinion in Pharmacology 2013, 13:576581

580 Immunomodulation

effects of oestrogen in a murine model of multiple sclerosis

[46]. As with neutrophils and macrophages, these actions of
oestrogen appear to be mediated largely through modulation of NFkB signalling and the inhibition of p65 nuclear
translocation [47], further reinforcing the importance of this
signalling pathway in the actions of oestrogen upon the
immune system.
Microglia have been more closely studied in terms of their
response to oestrogen, with many of their responses akin to
those of peripheral macrophages. For example, oestrogen
has been recently shown to inhibit accumulation of microglia following rat cerebral artery occlusion, through the
prevention of CCL2 and CCL5 secretion [48]. Similarly,
treatment of microglia with oestrogen has been shown to
prevent LPS-induced secretion of the pro-inflammatory
cytokines IL-1b and TNFa via activation of both ERa and
ERb [49], confirming a potent anti-inflammatory action of
the hormone. Evidence is accumulating that oestrogen is
not only anti-inflammatory, but may actually promote
resolution within the brain, as treatment of microglia with
oestrogen has been shown to potentiate their clearance of
apoptotic cells [50], an action vital for the efficient termination of an inflammatory reaction.

Conclusion
In this review we have identified several emerging mechanisms whereby oestrogen can affect the function of the
innate, adaptive and central immune systems, features
that are common to multiple components of these systems (summarised in Figure 2). In particular, oestrogen
has clearly been shown to interact with NFkB signalling
to limit inflammatory activity, along with accumulating
evidence for a role of the hormone in regulating the antiinflammatory/pro-resolution protein annexin A1. Whilst it
must be borne in mind that actions of oestrogen in one
cell type may not necessarily be transferable to another,
these pathways represent enticing new therapeutic targets, and reveal an opportunity to exploit this powerful
hormone to develop novel anti-inflammatory treatments.

Acknowledgements
We would like to thank Dr Neil Dufton for the illustrations in this review.
This review was supported by the British Heart Foundation (PG/09/060)
and The Wellcome Trust (086867/Z/08/Z).

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Current Opinion in Pharmacology 2013, 13:576581