From by guest on January 16, 2018.

Reviewarticle

The expanding role(s) of eosinophils in health and disease

Elizabeth A. Jacobsen,1 Richard A. Helmers,2 James J. Lee,1 and Nancy A. Lee3
1
Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, 2Division of Pulmonary Medicine, Department of Critical Care
Medicine, and 3Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ

Surprisingly, the role(s) of ing the role(s) of eosinophils in both that the collective reports in the
eosinophils in health and disease is health and disease demonstrates that literature showing a role for
often summarized by clinicians and the activities of these granulocytes are eosinophils in an everincreasing
basic research scientists as a far more expansive and complex than number of novel settings highlight
pervasive consensus opinion first previously appreciated. In turn, this
the true complexity and importance
learned in medical/graduate school. greater understanding has led to the
Eosinophils are rare white blood realization of this granulocyte. Indeed,
cells whose activities are primarily thateosinophilshavesignificantcontribut discussions of eosinophils are no
destructive and are only relevant in ory roles in a wide range of diseases. longer simple and more often than
parasitic infections and asthma. Furthermore, published studies even not now begin with the
However, is this consensus correct? implicate eosinophil-mediated activities question/statement “Did you know . .
This review argues that the wealth of in otherwise healthy persons. We .?”
available studies investigat- suggest (Blood. 2012;120(19):3882-3890)
Introduction
Hematology and medical text-books (eg, Hematology: Basic effector functions and to note the novel roles these cells may
Principles and Practice, 5th edition) often portray eosinophils have in the maintenance of homeostasis.
with 3 basic features: (1) they are nonspecific destructive and
cytotoxic cells; (2) eosinophils are an omnipresent cellular
infiltrate of the asthmatic lung; and (3) eosinophils are a
necessary and ubiquitous host defense against helminthic Eosinophils: agents of local tissue/organ immune
parasite infections.1,2 Thus, although this physician-scientist view regulation
of eosinophils is beginning to change (eg, Wintrobe’s Clinical
Eosinophils contain a full complement of mediators necessary to
Hematology, 12th edition), the widely held clinical perception of
regulate specifically both innate and adaptive immune responses.
these granulocytes is that they are “bad,” except for parasite
Many excellent review articles4,5 describe in great detail immune
clearance in patients, and even then, their function is only that of
mediators released by eosinophils and will not be reviewed in-
an end-stage destructive cell. That is, they are part of an innate
depth here. In brief, eosinophils express Th2 cytokines (eg, IL-4,
host defense strategy that recruits these cells to sites of parasitic
IL-5, IL-9, IL-13, and IL-25), Th1 cytokines (IL-12 and IFN-),
infection or as part of the dysregulated immune responses in the
acute proinflammatory cytokines (TNF-, IL-1, IL-6, and IL-8),
asthmatic lung, where they mediate nonspecific destruction of all
immune inhibitory cytokines (eg, TGF- and IL-10), and express
things (pathogen and host tissue alike). Consequently, the
receptors for many of these cytokines as well. 6,7 In addition,
tissue/organ pathology induced by their recruitment is nothing
eosinophils express molecules that directly modify T-cell
more than collateral damage of a mission accomplished (ie, host
activities through Notch pathways8 as well as costimulatory
defense). We will show that this perspective is outdated and
molecules (eg, CD80/86) and MHC class II that allow
problematic with a virtual explosion of recent studies
eosinophils to function as antigen-presenting cells. 9 Innate
highlighting previously unknown and/or underappreciated
immune activities of eosinophils include expression of pattern
eosinophil effector functions that emphasize a changing view of
recognition receptors, such as Tolllike receptors 1-5, 7, and 9,
eosinophils in health and disease.
nucleotide oligomerization domains 1 and 2, Dectin-1, and
This confounding paradigm-shift begs the question: What are
receptor for advanced glycation end products, which recognize
these cells really doing? This review highlights studies that
pathogen-associated molecular patterns or dangerassociated
suggest diverse and novel eosinophil effector functions (Figure
molecular patterns.10,11 Eosinophil granule proteins are also
1). Many of these functions are contained within our recently
capable of binding pattern recognition receptors in an autocrine
suggested paradigm that we have described as the “LIAR
and paracrine manner to induce cellular activation. Moreover,
hypothesis,” suggesting that instead of destructive end-staged
eosinophils express a host of immune modulating chemokines
effector cells, eosinophils are actually important regulators of
and adhesion molecules,12 complement receptors,13 and lipids and
local immunity and remodeling/ repair. 3 This hypothesis predicts
their receptors.14 In several examples cited below, these
the widening scope of eosinophil effector functions and suggests
previously underappreciated immune regulatory capabilities of
contributory roles of these granulocytes in both health and
eosinophils are highlighted as of potentially significant
disease. Our goal in this review is simply to continue this
importance in both health and disease.
“conversation” and summarize many of these new eosinophil
Submitted May 31, 2012; accepted August 15, 2012. Prepublished online as Blood First Edition paper,August 30, 2012; DOI 10.1182/blood-2012-06-
330845.
© 2012 by The American Society of Hematology
3882 BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19
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BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19 ROLES OF EOSINOPHILS IN HEALTH AND DISEASE 3883

Figure 1. The expanding roles of eosinophils in health and disease.

Eosinophils: tissue remodeling and repair neuropeptides,15 and cytokines such as IL-1 and IL-6.6,7
Furthermore, eosinophil release of secondary granule proteins,
Remodeling and repair are generally associated with permanent
eicosanoids, leukotrienes, reactive oxygen species, and cell-cell
structural and functional change from the original cellular and
signaling molecules have been hypothesized to contribute to
physiologic capacity of a cell, tissue, or organ. Thus, remodeling
remodeling events in both health (eg, bone metabolism 16) and
and repair includes, and is not limited to, extracellular matrix
various disease states. Manifestations of these activities in
breakdown and reformation, cellular transdifferentiation (eg,
disease states include increased fibrosis, vascular leakage,
transition of fibroblasts to myofibroblasts or Clara cells to goblet
angiogenesis, epithelial desquamation, epithelial metaplasia, and
cells in the respiratory epithelium), apoptosis/necrosis, cell
smooth muscle hypertrophy.17-19 As such, reports in the literature
proliferation, and altered cellular activation. These events are
have linked eosinophils with the remodeling events and
initiated by the release of growth factors, cytokines, chemokines,
structural changes occurring in prominent eosinophilassociated
enzymes, lipid mediators, and reactive oxygen species from the
conditions as well as more obscure (ie, not necessarily
tissue or infiltrating inflammatory cells. Eosinophils have been
eosinophil-associated) diseases.
demonstrated to express and release both mediators of epithelial-
mesenchymal transition, such as TGF-, basic fibroblast growth
factors, plateletderived growth factor, matrix metalloproteases,
vascular endothelial growth factors4,5,11 as well as other
repair/remodeling factors, such as nerve growth factors,
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3884 JACOBSEN et al BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19

Classic eosinophil diseases with novel roles characterized as destructive.2 As a result, their presence in
Eosinophils and parasites: not necessarily host defense but airways was suggested to increase and/or cause the symptoms
instead symbiotic partners occurring in asthma patients (eg, airways hyper-responsiveness).
This suggestion was also supported in many mouse models of
Eosinophils are a common proinflammatory cell infiltrate during
allergic respiratory inflammation, including a transgenic model
helminth infection and are often considered necessary for
of severe asthma where induced pulmonary pathology was
parasite killing.1 For example, animal model studies have noted
directly linked with one or more eosinophil-mediated effector
that eosinophils are directly recruited within hours to days after
functions.31 However, improvement of symptoms in asthma
tissue infiltration of parasites and appear to participate in the
patients after therapies targeting eosinophils have not been linear
killing of the parasite through the release of toxic eosinophil
and have been met with limited success, 32,33 suggesting that a
effector mediators, such as major basic protein 20 and reactive
much more complex relationship between eosinophils and
oxygen species.21 However, other studies using eosinophil-
induced lung pathology exists. A potentially greater
deficient mice (eg, dblGATA-122 and PHIL23) have demonstrated
understanding of how eosinophils may contribute to asthma (ie,
virtually no difference in worm burden in the presence or
allergic respiratory inflammation) was achieved with the
absence of eosinophils.24 These data suggested that, although
demonstration that eosinophils have the ability to regulate
eosinophils have a more active “killing” role in some parasitic
immune responses through direct effects on T-cell activities in
infections,25 other nonlethal activities of significance nonetheless
mouse models of asthma. A brief review of these studies
exist, leading investigators to underappreciate the true extent of
provides the necessary context for the evolution of this new
eosinophil effector functions.
paradigm correlating the spatial distribution of eosinophils and
Recent studies by Gebreselassie et al 26 and Fabre et al27 in the
their immune regulatory roles.
mouse may have provided a solution to this quandary, suggesting
Several reports have proposed and tested various mechanisms
a unique role for eosinophils not in parasite killing but instead
that would explain the potential modulation of T-cell activities
for parasite survival. Specifically, Trichinella spiralis has a 2-
by eosinophils. The unique ability(ies) of eosinophils to elicit the
stage life cycle whereby newborn larvae convert a muscle cell
local recruitment/accumulation of allergen-specific effector T
into a nurse cell for the developing parasite. This nurse cell is
cells on allergen exposure were demonstrated in 2 independent
surrounded by macrophages in a manner mimicking granuloma
studies.34,35 In addition, eosinophils have been uniquely shown to
formation required by all parasites,28 allowing the parasite to
contribute to the activation of antigen-specific memory T cells
remain quiescent in its host for months to years. In the absence
(promoting their proliferation) and function as agents that
of eosinophils, the number of nurse cells is dramatically reduced
polarize on-going T-cell responses. This ability of eosinophils to
in infected mice.27 Furthermore, in the absence of eosinophils,
promote T-cell activation/ proliferation (ie, display dendritic cell
infiltrating Th2 T cells are reduced and recruited macrophages
[DC]-like activities) was initially outlined in studies using both
have enhanced iNOS expression,26 suggesting that, in the absence
mouse models of asthma as well as in vitro assays on patient
of eosinophilmediated Th2 cytokine production, iNOS-
samples. Specifically, these studies suggested that eosinophils
expressing inflammatory macrophages (M1 type) outnumber the
may function as costimulatory cells acting on both primed and
alternatively activated macrophages (M2 type). The resulting
naive T cells.9 Clearly, mechanistic studies involving human
excessive host inflammatory responses led to the death of the
asthma subjects have lagged behind the pace at which these
resident parasite and, in turn, significant muscle
insights have been revealed in the mouse. For example, mouse
pathology/necrosis. The failure of nurse cells to thrive in
eosinophils have been shown to process and present antigen via
eosinophil-deficient mice was rescued by intravenous transfer of
MHC class II36,37 and induce Th2 cytokine production from
eosinophils into the mice, 26 demonstrating a direct role for
antigen-specific CD4 T cells.36,38 Moreover, eosinophils were
eosinophils in aiding helminth survival while at the same time
demonstrated to migrate to lung draining lymph nodes in mice
dampening the inflammatory response of the host. The
with similar kinetics to DCs and reside in the T-cell rich zone. 39,40
mechanisms of this eosinophil-mediated macrophage regulation
It is noteworthy that more recent studies in mouse models of
remain to be defined, yet studies by Stolarski et al that
asthma have since demonstrated that, although eosinophils have
demonstrated eosinophil release of IL-4 and IL-13 polarized
the capacity to act as antigen-presenting cells, DCs are still likely
macrophage toward an M2 phenotype suggest a mechanism by
to be the predominant MHC class II antigen-presenting cell that
which eosinophils directly modulate local Th2 polarization
results in proliferation of T cells 41,42 with eosinophils contributing
conditions to protect the resident parasite. 29 Consequently,
to the polarization of the in vivo immune responses occurring in
eosinophils may be interpreted as being part of a strategy to
the lung.43
achieve homeostasis allowing the parasite to reside in the host
Jacobsen et al have recently identified an additional
with limited pathologic consequences to either the parasite or
eosinophilmediated effect on T-cell activities, suggesting that
host, a conclusion that represents a return to the conclusions of
eosinophils are not replacements for DCs but instead are third
earlier studies suggesting that recruited eosinophils contain (ie,
party cells necessary for DC-mediated T-cell proliferation and
limit) ongoing inflammatory events.30
subsequent Th2 polarization.43 These investigators expanded on
Eosinophils and asthma: not necessarily destructive effector earlier studies by Niu et al 44 and Hammad et al42 demonstrating
cells mediating lung pathology but instead modulators of the requirement of a non-DC (but MHC class II expressing) cell
pulmonary immune responses to allergen that was necessary for the T-cell proliferation and polarization
induced by DC-mediated antigen presentation. In particular,
Eosinophils have been viewed as omnipresent inflammatory cells
Jacobsen et al showed that adoptive transfer of eosinophils into
whose role in asthma, although not clearly defined, has been
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BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19 ROLES OF EOSINOPHILS IN HEALTH AND DISEASE 3885
eosinophil-deficient animals during allergen challenge resulted augment secondary immunization of plasma B cells enhancing
in recruitment of antigenpresenting myeloid DCs to those lymph their long-term antibody production.53 Eosinophil roles in bone
nodes and also in the subsequent Th2 polarized character of the marrow may also include remodeling events, such as bone
immune response. Significantly, these data demonstrated that regeneration through release of IL-4 and IL-6. 16 Currently, these
eosinophils polarize the T-cell response to Th2 by a unique investigations have been confined to a limited number of models
pathway; it appeared that eosinophils promoted the suppression of long-term humoral memory responses in mice and await
of Th1 and, in particular, Th17 responses. Although the further studies in patients. In addition, significant perturbations
mechanisms have not been defined, eosinophil-released in short-term humoral immune responses have not been reported
cytokines may be directly affecting T cell or DC responses in eosinophil-less strains of mice and again the relationship
through release of Th2 cytokines (eg, IL-4 and IL-25) or between eosinophils and plasma B cells in humans remains
suppressive mediators (eg, IL-10, indoleamine-2 3-dioxygenase unclear. However, if such a link were established in patients,
[IDO], and TGF-). In addition, other studies have demonstrated these observations would have potentially significant
that human eosinophils are capable of modulating DC migration implications for many diseases that result from abnormal
and activation.45 Thus, in mice, and possibly humans, eosinophils expression of antibodies by plasma B cells (eg, autoimmune
may contribute to the polarization of immune responses by diseases or multiple myeloma).
directly modulating T cells and/or indirectly by influencing DC-
Thymic development and T-cell selection
mediated activities.
It is interesting to speculate that the blockade of Eosinophils were first described to localize to the thymus in the
eosinophilmediated immune regulation may also provide an 1970s54 and since have been characterized as increasing to a
explanation for the efficacy of inhaled corticosteroids and anti– maximal level within 2 weeks of age in mice 55 and 2-3 years in
IL-5–based treatments in both human subjects with asthma (ie, humans.56 The presence of eosinophils within the
mepolizumab32,33 and benralizumab46) and mouse models of corticomedullary and medullary region have suggested that these
allergic respiratory inflammation.47,48 That is, in both species the cells may participate directly in the selection of T cells or may
eosinophil-targeting effects of these agents may not only prevent aid in the scavenging of dead cells that fail negative selection.
tissue damaging effector functions but also disrupt eosinophil- Throsby et al characterized these mouse-derived eosinophils as
mediated immune regulatory pathways. Clearly, further studies CD11cint, CD11bhi, CD44hi cells that express TGF-, IL-4, and IL-
are necessary in both asthma patients and mouse models to 13 and are capable of acute class 1-dependent negative selection
confirm the potential commonality of eosinophil activities in of T cells.55 In a recent study, Moqbel et al demonstrated in
allergic pulmonary diseases. surgically removed thymus of neonates and children that
eosinophils express IDO, IL-4, and IL-13; this expression was
Eosinophilic esophagitis also shown to decrease with age. 56 They suggest that the IDO-
Eosinophilic esophagitis is a significant cause of dysphagia and positive eosinophils contribute to the Th2 character of the
food impaction in adults and is also linked with vague symptoms developing thymus in normal humans by inducing apoptosis of
previously associated with gastroesophageal reflux disease in Th1 cells through depletion of tryptophan. An alternative
children.49 Predictably, eosinophilic esophagitis has been function of eosinophils in the thymus was demonstrated recently
mechanistically linked in both human subjects 50 and mouse by Kim et al that suggests eosinophils aid macrophages in the
models51 with eosinophil agonists, such as IL-5 and eotaxin phagocytosis of apoptotic thymocytes induced by -irradiation. 57
chemokines. Although the consensus in the literature is that Despite this circumstantial evidence linking eosinophils and the
eosinophils are omnipresent in this disease and likely to have thymus, it is interesting that pathologies that would be linked
one or more causative role(s), the importance of their presence or with T-cell selection in vivo (eg, systemic autoimmune disease)
individual activities has remained unresolved. have not been reported in eosinophil-less strains of mice. Thus,
the suggestion that eosinophils have a functional role in T-cell
selection in the thymus of both humans and mice remains a
provocative yet still unproven hypothesis.
Novel eosinophil roles in health
Metabolic syndrome: adipose, insulin, and inflammation
Eeosinophils and plasma cell survival
Metabolic syndrome is characterized by an increased risk of
Long-term memory in humoral immunity is acquired by the
atherosclerosis, stroke, and type 2 diabetes. Defining the
survival and continued function of plasma B cells to generate
regulation of inflammatory pathways and metabolic signals is a
antibody against pathogens. A novel study by Chu et al
complex problem to undertake, yet individual findings in clinical
demonstrated a role for eosinophils in plasma B-cell survival in
studies58 and use of animal models59 have suggested a potential
the bone marrow.52 Specifically, these investigators found that by
role for eosinophils in maintaining metabolic homeostasis. In
immunizing eosinophil-deficient mice (PHIL or dblGATA1) or
particular, studies in mice have highlighted a role for
mice depleted of eosinophils by using anti-SiglecF antibodies
eosinophils59 in modulating adipocyte tissue macrophages, which
resulted in a reduced number of antigen-specific plasma B cells
are important in metabolic homeostasis. 60 Specifically, Wu et al
in the bone marrow of these mice. Eosinophils were
demonstrated that resident eosinophils in adipose tissue appear
demonstrated to reside near marrow plasma B cells and produce
to mediate macrophage differentiation to the M2 phenotype,
APRIL and IL-6, suggesting eosinophils were contributory to
increase M2 cell numbers in fat, and are required for glucose
plasma B-cell survival through these cytokines. Moreover, in a
homeostasis (ie, normal insulin sensitivity). 59 Furthermore, they
second paper, Chu et al demonstrated that eosinophils may
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3886 JACOBSEN et al BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19

demonstrated that eosinophil numbers in fat tissue correlate from T cells, also demonstrated attenuated mammary bud
inversely with fat deposition in animal models, suggesting that development,70 in this case, presumably because the
the presence of eosinophils is protective toward development of inflammatory infiltration of eosinophils to the mammary tissue
type 2 diabetes. Collectively, these studies hypothesize that disrupting homeostatic development. The unresolved question is
eosinophils resident to adipose tissue aid in the polarization of the translational character of these observations to humans.
the immune microenvironment (eg, differentiation of
macrophages to the M2 phenotype) needed to sustain glucose Responses to respiratory viral infection
and insulin homeostasis. These new findings for eosinophil
Respiratory viruses have become a burgeoning area of research
function in mouse glucose homeostasis have yet to be examined
in the pulmonary field because of their suspected causative
in otherwise normal patients and patients with metabolic
effect(s) on asthma development and exacerbations. 71 The link
syndrome.
between eosinophils, respiratory viruses, and asthma appears to
Female reproductive system be complex but several observations are noteworthy suggesting a
commonality of the role(s) of eosinophils in both humans and
Physiologic functions of the mammalian female reproductive
mice in response to viral infections: (1) Formalin-inactivated
tract are regulated, in part, by remodeling events induced by
respiratory syncytial virus vaccine provided to children in the
resident and infiltrating leukocytes, suggesting a functional role
1960s led to a hypersensitivity response that induced
for inflammatory-like processes.61 Eosinophils are found in both
eosinophilia.72 In animal models, viral exposure after vaccination
the developing ovary and increased in numbers in preovulatory
was demonstrated to lead to what was described as a Th2
follicles, possibly via eotaxin- or RANTES-dependent
cytokine bias with an associated eosinophilia, although the role
recruitment.62 The potential role of eosinophils in the ovary is
of these eosinophils remains controversial. 73 (2) Respiratory viral
purely speculative at this point; however, the demonstration that
infections in the first few years of life are often associated with
eosinophils are robust sources of the same remodeling factors
an increased incidence of asthma and a correspondingly induced
noted to be required during the transition from follicle to luteal
pulmonary eosinophilia. Yet specific mechanisms remain the
phase is highly suggestive.
subject of debate.71 Moreover, studies have suggested a number
Pregnancy. Eosinophils have been shown to be a significant
of immune pathways linking eosinophils, viral inducedasthma,
cellular infiltrate of the placenta and uterus, 63 including the
and asthma exacerbations, but these remain to be clarified in
infiltration and degranulation of eosinophils in cervix of
both patients and in mouse models of respiratory infection. 74,75
pregnant humans.64 Timmons et al have suggested that the
(3) Ex vivo studies using purified proteins in both viral infection
increased presence of eosinophils in the cervix permits dilation
studies in culture and several in vivo animal studies of viral
for birth and postpartum remodeling.65 The observation that
infection have mechanistically linked antiviral eosinophil
eosinophil infiltration of the cervix is also associated in time and
activities to the release of secondary granule proteins. These
location with the increased presence of activated macrophages 65
include the demonstration that eosinophil-associated
suggests that eosinophils may contribute not only to the
ribonucleases displayed antiviral activities toward single-
remodeling of the cervix directly, but may do so indirectly
stranded RNA viruses,76 the observations that major basic
through the polarization of macrophages in the cervix.
protein77 and eosinophil peroxidase (EPX)78 each appear to
Endometriosis. During mammalian estrus, uterine provide unique antiviral activities in mouse models of viral
eosinophils are normally absent during the menstrual cycle infection, and eosinophil activation may be linked with the
except during menstruation.66 Menstruation is an acute binding of viral ligands to Toll-like receptors on
inflammatory response, yet chronic inflammation (particularly
eosinophils.79
when it occurs at ectopic sites) results in endometriosis and is a
In summary, these studies suggest that eosinophils in both
prominent cause of female infertility. Interestingly, observations
humans and mice may have a potential contributory role(s) to the
showing a concordance of eosinophil infiltration/eosinophil
immune responses associated with viral vaccination/infection as
degranulation with fibrotic regions of endometriotic tissue 67
either a fundamental innate host response to viral infection, a
suggest a potential role for eosinophils in the remodeling and
component of acquired immune responses to viral infection,
fibrosis that occurs in this inflammatory disease.
and/or a contributor to host remodeling/repair required in the
Mammary gland development recovery phase post-infection.

Eosinophils are associated with terminal end buds of the Pulmonary hypertension
developing mammary gland and appear to be a required
component of terminal end budding and ductal branch Pulmonary hypertension is characterized by the restriction of
morphogenesis. Specifically, Gouon-Evans et al demonstrated arterial blood vessels within the lungs, leading to impaired
that macrophages are essential for the development of terminal oxygen exchange. Weng et al used a novel mouse model that is
end buds during development in mice and that eosinophil deficient in a cytokine secreted by adipose tissue, adiponectin, to
recruitment depends on the expression of eotaxin-1. 68 The show a unique connection between pulmonary hypertension and
importance of these eosinophilmediated remodeling events in the eosinophils.80 Specifically, airways allergen provocation of
mammary gland development were foreshadowed by our adiponectindeficient mice (adn /) that were also eosinophil-
observations of decreased litter size and weanling survival in IL- deficient resulted in attenuated pulmonary hypertension as well
5–deficient nursing dams.69 Alternatively, excessive numbers of as decreased remodeling of the lung vasculature. 80 More
eosinophils, such as in hypereosinophilic mice that express IL-5 importantly, they were also able to demonstrate directly that
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BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19 ROLES OF EOSINOPHILS IN HEALTH AND DISEASE 3887
eosinophil granule products are able to induce arterial smooth ability of eosinophils to engage in remodeling/repair and to
muscle proliferation in vitro, suggesting eosinophils are essential modulate the immune microenvironment supports a suggested
for the vasculature remodeling that leads to pulmonary paradigm in which these granulocytes contribute to post-
hypertension. The hypothesis proposed is that eosinophils transplant organ homeostasis.
release angiogenic and vascular remodeling mediators, such as
vascular endothelial growth factor and TGF-, which increases IBD
extracellular matrix remodeling and vascular inflammation.
Inflammatory bowel diseases (IBD), such as Crohn disease and
Significantly, Puxeddu et al have also demonstrated that
ulcerative colitis, are characterized by significant inflammation
eosinophils have the capacity for endothelial remodeling. 81 The
and tissue remodeling in the small intestine and colon,
association of eosinophils and pulmonary hypertension thus far
respectively, resulting in diarrhea, constipation, and weight loss
is limited to mouse-based studies. Nonetheless, these studies are
in patients.90 Although eosinophils are found in the
suggestive that a similar association may represent and
gastrointestinal tract at baseline (stomach to rectum 91), their
underappreciated pathway occurring in human subjects.
numbers and their degranulation are dramatically increased in
IBD.92 Mouse models of IBD have also provided important
Acute lung injury
insights showing that eosinophils are potential contributors to the
Acute lung injury are related pulmonary conditions associated inflammation and remodeling that occur in these diseases. For
with significant lung histopathologic changes ultimately example, disease progression in spontaneous mutant mice that
resulting in an inability to exchange oxygen sufficiently, mimic IBD disease in humans (ie, SAMP mutations) are
increasing patient risk of mortality and morbidity. These diseases attenuated by depletion of eosinophils (administration of IL-5 93
are often idiopathic and linked with a multitude of factors, or chemokine receptor 394 antibody). It is once again noteworthy
including exposure to toxic chemicals, infection/sepsis, and that in these mouse models of IBD, depletion of eosinophils also
complications of other diseases. Although acute lung injury is resulted in a reduction in the number and activation of effector
generally not thought of as an eosinophilic disease, 82 Willetts et CD4 Th2 T cells in the draining lymph nodes and their ability to
al demonstrated that increased numbers of eosinophils are be activated on stimulation. 93 Similarly mice deficient in IL-5, 95
associated with survival of acute lung injury patients, suggesting EPX,95 and eosinophils96 are partially protected from chemical-
a potential diagnostic value of assessing for eosinophils and their induced models of colitis. We would suggest that the remarkably
associated activities in these patients. 83 complex immunity of the gut occurring as a consequence of the
bacterial burden of this compartment (and the necessary
Transplant rejection containment it requires of the host) may explain why uniquely
the gastrointestinal tract has a rather robust resident eosinophil
Transplant rejection (ie, GVHD) is an acute or chronic population. Interestingly, although the primary function of these
inflammatory/ remodeling phenomenon that ultimately results in eosinophils may be immunoregulative in character, recent
destruction of the transplanted cells/tissue and increased observations of unique antibacterial activities97,98 may be equally
mortality and morbidity. Significantly, intact and degranulated underappreciated effector functions of these gut-associated
eosinophils have been demonstrated to localize to rejected granulocytes.
human donor tissue in a variety of organs (eg, kidney 84 and
heart85). Currently, the role of eosinophils in these cases has Duchenne muscular dystrophy
primarily been limited to that of a marker for acute GVHD
without a thorough understanding of the role that eosinophils Duchenne muscular dystrophy is a genetic mutation in
may play. Several possibilities exist, including that the dystrophin that leads to mechanical injury of the muscle tissue
eosinophil infiltrate is an inflammatory “consequence” of the over time followed by the infiltration of activated leukocytes.
complex immunobiology surrounding host responses to the The ensuing inflammation has been proposed to lead to tissue
transplant or that eosinophils are immune cells actively fibrosis and mechanical failure of the muscle often leading to
maintaining homeostatic transplant integrity. Alegre et al death as a consequence of cardiac failure. A key (yet largely
suggested multiple immune mechanisms of GVHD whereby unexplained) feature of Duchenne muscular dystrophy is the
eosinophils predominate as the mediators of Th2-induced eosinophil accumulation occurring in the injured muscle and its
rejection.86 For example, studies have demonstrated that in correlation with disease severity.99 Significantly, Wehling-
Th1/IL-17–deficient mouse models of organ transplant, 87 Henricks et al have demonstrated, using a mouse model of
eosinophil infiltration into the tissue was a predominant feature. Duchenne muscular dystrophy (ie, dmx/), that eosinophils appear
Moreover, the absence of IL-5 or eosinophils (antibody to contribute to the disease process through the deposition of
depletion) attenuated transplant rejection in MHCincompatible major basic protein, which resulted in both site-specific fibrosis
allograft transplant models.88,89 The novelty of these observations and induced changes in inflammatory immune responses leading
is again that eosinophils may promote and/or amplify Th2 to disease-specific muscle pathologies.100
immune responses associated with organ/tissue rejection. In
addition, depletion of eosinophils in mice (administration of Eosinophil-nerve interactions leading to twitch and itch
antibody to IL-5) that develop chronic GVHD after cardiac
transplant led to reduced collagen and elastin deposition, 88 Eosinophil-nerve interactions have been documented in the
suggesting a direct role for eosinophils in the fibrotic processes literature and represent a collection of studies that suggest an
(ie, remodeling/repair) linked with transplant rejection. Thus, the underlying importance as part of the potential
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3888 JACOBSEN et al BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19

remodeling/immune events contributing to tissue-nerve independent mechanisms potentially linking eosinophils and
homeostasis. Two areas of translational research investigating cancer: (1) The recruitment of eosinophils is probably a host
the potential clinical implications of eosinophil-nerve inflammatory response to the tumor as a consequence of cell
interactions are worth noting as they highlight the complexity of death/necrosis and/or hypoxia that elicits the release of
these events as well as their possible significance in health and dangerassociated molecular patterns. 111 This perspective suggests
disease. In the first area, Costello et al have demonstrated that that eosinophils are a component of innate host defense to a
eosinophils/eosinophil granule proteins in both human perceived threat, leading to remodeling/repair that may increase
biopsies,101 and guinea pig models of allergic respiratory or decrease tumor growth. (2) Tumor infiltrating eosinophils are
inflammation102 are often found in proximity of parasympathetic part of host immune responses that include abilities to polarize
nerves and may lead to an inhibition of acetylcholine binding as T-cell functions, modulate humoral responses, or even be
part of a negative feedback loop modulating airway smooth immunosuppressive in character. For example, the presence of
muscle tone.103 Localization of eosinophils to these IDO-positive eosinophils,112 release of eosinophil granule
parasympathetic neurons may be through eotaxin released by proteins,113 and the presence of IL-5114 have all been shown to be
neurons,104 and subsequent eosinophil-nerve interactions may be protumorigenic, whereas in other instances eosinophils are
direct in character as eosinophils have been shown to express antitumorigenic.115 Indeed, animal studies addressing the relative
classic neuromediators, such as neuropeptides and neurotrophins role of eosinophils have been confounding. 115,116 Regardless of
as well as their receptors. 15 In the second area of research the specific role(s) eosinophils have in cancer, these eosinophil-
regarding eosinophil-nerve interactions, Foster et al have mediated activities (either remodeling/repair or
demonstrated that degranulating eosinophils in humans immunoregulatory) are clearly not bystander effects, and these
colocalize with nerves of the dermis and increased with the cells probably contribute both potentially significant
severity of contact dermatitis. 105 Studies with eosinophil-less protumorigenic and/or antitumorigenic activities.
PHIL mice and mouse models of contact dermatitis have
recently confirmed a link among eosinophils, nerve growth and
branching, and increased levels of itch response (J.J.L., Eosinophils: biomarkers in translational strategies of
unpublished observations, July 2012). Collectively, these patient care
observations suggest eosinophil-nerve interactions first identified
in the lung may also exist in other tissue compartments with The classic example of eosinophils as a biomarker for disease
consequences to nerve function in other tissues. and severity is in the diagnosis of asthma and asthma
exacerbations. In this example, elevated levels of eosinophils in
sputum (as detected by hematoxylin and eosin-stained
Multiple sclerosis and neuromyelitis optica
differentials) correlate with disease severity and can be used in
Multiple sclerosis and neuromyelitis optica are diseases of the management of patient care. 33 However, novel assays with
demyelination of the CNS with progressive or the ability to identify and quantify eosinophil activities are now
remitting/relapsing occurrence. Multiple sclerosis primarily beginning to show promise as diagnostic tools. For example, we
involves the brain and spinal cord and is considered a Th1/Th17 have demonstrated, through the use of a novel anti-eosinophil
autoimmune disease. Mouse models of multiple sclerosis peroxidase monoclonal antibody (EPX-mAb), that this detection
(experimental allergic encephalomyelitis) generated by method was capable of identifying tissue infiltrating eosinophils
immunizing animals with myelin protein peptides also have in patient biopsies, as well as evidence of degranulation, that was
demonstrated a role (although largely undefined) for Th2 significantly beyond the ability to do so through conventional
cytokines (eg, IL-4106 and IL-5107), and possibly eosinophils in evaluations of hematoxylin and eosin-stained slides. 83,117 In
disease suppression. Neuromyelitis optica is a similar disease addition, biochemical assays of eosinophil activities 118 and
now thought to be an autoimmune reaction to aquaporin-4 eosinophil granule proteins have been used as novel assays to
targeting the
spinal cord and link eosinophil activities to disease severity and/or
optic nerve. Significantly, eosinophils are elevated in the optic
lesions of patients with neuromyelitis optica, and CSF displays References
increased Th2 cytokines and the presence of eosinophil granule patient outcomes as is true of unique ELISA assays of eosinophil
proteins.108,109 granule proteins (eg, EPX119). The availability of these novel
Cancer and tumor biology methodologies is of particular interest moving forward as the
Regardless of the diverse etiology of cancers, eosinophils are a roles of eosinophils expand from the “classic” eosinophil-
common cellular infiltrate found in nearly all solid tumors and associated diseases of asthma and helminth infection to the
cancers of epithelial origin. Examples of eosinophil-containing myriad of diseases and pathologies linked with eosinophils.
cancers in humans3 include, and are not limited to In conclusion, remarkably, over the past 10 years, the list of
gastrointestinal, uterine, cervical, mammary, bladder, eosinophil-associated diseases has neither narrowed nor
glioblastoma, pancreatic, and oral. 3,110 Although eosinophil remained the same. Instead, this list has dramatically grown and
infiltration of tumors is common, the cause and consequences seems to be limited only by the curiosity and cleverness of
(ie, protumorigenic vs antitumorigenic) of this recruitment and investigators caring for patients or studying particular diseases.
accumulation are unclear. Recent studies in mouse models of In addition, the same can be said of more basic research studies
cancer and patient biopsies have suggested 2 somewhat defining eosinophil effector functions and their potential roles in
 From www.bloodjournal.org by guest on January 16, 2018. For personal use only.

BLOOD, 8 NOVEMBER 2012 VOLUME 120, NUMBER 19 ROLES OF EOSINOPHILS IN HEALTH AND DISEASE 3889
the molecular and cellular processes underlying homeostasis. N.A.L.), American Heart Association (11SDG7510043; E.A.J.),
Thus, when asked about the roles of eosinophils in health and and Mayo Foundation for Medical Education and Research.
disease, it now seems appropriate to begin any discussion with
“Did you know . . .?”
Authorship
Contribution: E.A.J., J.J.L., and N.A.L. conceived, developed,
Acknowledgments
and wrote the review; and R.A.H. provided essential clinical
The authors thank persons from within Lee Laboratories not insights and perspective.
listed as authors for invaluable contributions, including Dr Conflict-of-interest disclosure: The authors declare no
Sergei Ochkur, Dr Rachel Condjella, Alfred Doyle, and Dr competing financial interests.
Michael McGarry; friends within the community who for years Correspondence: James J. Lee, Mayo Clinic School of
have provided us with ideas and thoughtful reflection in our Medicine, Department of Biochemistry and Molecular Biology,
quest of trying to understand all things eosinophil; Mayo Clinic Mayo Collaborative Research Building, Mayo Clinic Arizona,
Arizona medical graphic artist Marv Ruona and Joseph Esposito 13400 E Shea Blvd, Scottsdale, AZ 85259; e-mail:
of Research Library Services for their tireless efforts; and the jjlee@mayo.edu; and Nancy A. Lee, Mayo Clinic School of
Lee Laboratories administrative staff (Linda Mardel and Charlie Medicine, Department of Biochemistry and Molecular Biology,
Kern), without whom we could not function as an integrated Mayo Collaborative Research Building, Mayo Clinic Arizona,
group nor achieve the degree of success that we have 13400 E Shea Blvd, Scottsdale, AZ 85259; e-mail:
experienced. nlee@mayo.edu.
This work was supported by the National Institutes of Health
(grants HL065228 and RR109709, J.J.L.; grant HL058723,
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2012 120: 3882-3890

doi:10.1182/blood-2012-06-330845 originally published
online August 30, 2012

The expanding role(s) of eosinophils in health and disease

Elizabeth A. Jacobsen, Richard A. Helmers, James J. Lee and Nancy A. Lee

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