Allergology International 66 (2017) 382e391

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Allergology International
journal homepage: http://www.elsevier.com/locate/alit

Invited review article

Emerging roles of basophils in allergic inflammation

Kensuke Miyake*, Hajime Karasuyama
Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Basophils have long been neglected in immunological studies because they were regarded as only minor
Received 3 April 2017 relatives of mast cells. However, recent advances in analytical tools for basophils have clarified the non-
Received in revised form redundant roles of basophils in allergic inflammation. Basophils play crucial roles in both IgE-dependent
12 April 2017
and -independent allergic inflammation, through their migration to the site of inflammation and
Accepted 13 April 2017
Available online 11 May 2017
secretion of various mediators, including cytokines, chemokines, and proteases. Basophils are known to
produce large amounts of IL-4 in response to various stimuli. Basophil-derived IL-4 has recently been
shown to play versatile roles in allergic inflammation by acting on various cell types, including macro-
Keywords:
Basophil
phages, innate lymphoid cells, fibroblasts, and endothelial cells. Basophil-derived serine proteases are
IgE-mediated chronic allergic inflammation also crucial for the aggravation of allergic inflammation. Moreover, recent reports suggest the roles of
IL-4 basophils in modulating adaptive immune responses, particularly in the induction of Th2 differentiation
Protease and enhancement of humoral memory responses. In this review, we will discuss recent advances in
Th2 differentiation understanding the roles of basophils in allergic inflammation.
Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
Abbreviations: article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
5-LOX, 5-lipoxygenase; AD, atopic
dermatitis; APC, antigen-presenting cell;
APRIL, a proliferation-inducing ligand;
BAFF, B cell-activating factor; CIU, chronic
idiopathic urticaria; COX, cyclooxygenase;
DC, dendritic cell; DT, diphtheria toxin;
EGF, epidermal growth factor;
EoE, eosinophilic esophagitis;
EMA, European Medicines Agency; FcRg, Fc
receptor common g-chain; FDA, Food and
Drug Administration; GFP, green
fluorescence protein; GPCR, G protein-
coupled receptor; IgE-CAI, IgE-mediated
chronic allergic inflammation; ILC2, group 2
innate lymphoid cell; Lm, Listeria
monocytogenes; LPS, lipopolysaccharide;
MHC-II, major histocompatibility complex
class II; mMCP-11, mouse mast cell protease
11; Nb, Nippostrongylus brasiliensis;
OVA, ovalbumin; PAF, platelet-activating
factor; PGN, peptidoglycan;
PspA, pneumococcal surface protein A;
SLE, systemic lupus erythematosus;
TLR, Toll-like receptor; Treg, regulatory T
cell; TSLP, thymic stromal lymphopoietin;
VCAM-1, vascular cell adhesion molecule-1;
WT, wild-type

Introduction
* Corresponding author. Department of Immune Regulation, Graduate School of
Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45
Basophils are the least common granulocytes, representing less
Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
E-mail address: miyake.mbch@tmd.ac.jp (K. Miyake). than 1% of peripheral blood leukocytes in both mice and humans.
Peer review under responsibility of Japanese Society of Allergology. Basophils share some features with tissue-resident mast cells,

http://dx.doi.org/10.1016/j.alit.2017.04.007
1323-8930/Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391 383

including basophilic granules in their cytoplasms and expression of
the high-affinity IgE receptor FcεRI on their cell surfaces.1 There-
fore, basophils have long and erroneously been considered to serve
redundant roles with mast cells. Nevertheless, basophils and mast
cells differ in several aspects, including their localization and life
span.1,2 Basophils circulate in the peripheral blood and migrate to
sites of inflammation, whereas mast cells reside in the peripheral
tissues and are rarely detected in blood. Moreover, the life span of
basophils (~60 h) is much shorter than that of mast cells (2e3
weeks). Despite these differences that suggest functional differ-
ences between basophils and mast cells, the non-redundant roles of
basophils have not been identified until recently, partly because of
the rarity of basophils and lack of tools for basophil research. The
recent development of novel analytical tools, including basophil-
depleting antibodies and genetically-engineered mice deficient
for basophils, have revealed non-redundant functions of basophils
in various immune responses such as chronic allergic inflammation
and protective immunity against parasites.3e5 Moreover, a recent
report showed that expression profiles of basophils are much
different from those of mast cells,6 indicating their distinct roles in
immune responses. In this review, we focus on recent advances in
our understanding of basophils in allergic inflammation.
Roles of basophils in allergic inflammation
IgE-dependent allergic inflammation
IgE-mediated chronic allergic inflammation(IgE-CAI) in the skin
Infiltration of basophils into inflammatory sites has been re-
ported in various types of allergic inflammation, including atopic
dermatitis, allergic rhinitis, and asthma.7e9 However, until recently,
the contribution of basophils in allergic reactions has remained
obscure. Our group has identified non-redundant roles of basophils
in a mouse model of IgE-CAI.10e12
In this model, mice were passively sensitized with antigen-
specific IgE and then their ears were subcutaneously injected with
antigens. Consequently, mice exhibited mast cell-dependent
biphasic ear swelling (comprising immediate-phase and late-
phase ear swelling), followed by severe ear swelling that peaked
on days 3e4 after challenge. This delayed-onset ear swelling
accompanied massive infiltration of inflammatory cells, including
eosinophils, neutrophils, and macrophages, and hyperplastic
epidermis with hyperkeratosis. We designated this delayed-onset
response IgE-CAI. IgE-CAI can be elicited even in the absence of
mast cells or T cells, suggesting that neither mast cells nor T cells are
essential for the development of IgE-CAI. Importantly, adoptive
transfer of basophils into FcεRI-deficient mice can reconstitute IgE-
CAI, even though basophils account for only ~2% of skin-infiltrating
cells, demonstrating the pivotal role of basophils in this reaction.
Later studies further confirmed the indispensable role of basophils
in IgE-CAI by using basophil-specific depletion antibody (anti-
CD200R3 antibody (Ba103)) or genetically engineered-mice that
specifically lack basophils (Mcpt8Cre mice, diphtheria toxin (DT)-
treated Mcpt8DTR mice, and DT-treated Bas-TRECK mice).11e14
Notably, depletion of basophils even during the progress of
inflammation resulted in the suppression of ear swelling and a
drastic reduction in inflammatory cell infiltration, suggesting the
effectiveness of basophil-targeted therapy.11 Therefore, basophils
appear to act as initiators of inflammation, recruiting other in-
flammatory cells such as eosinophils and neutrophils. We postulate
the following scenario in IgE-CAI pathogenesis (Fig. 1); First, a small
number of basophils are recruited to skin lesions by unknown
mechanisms. IgE-bound basophils are activated by antigens,
causing the release of various inflammatory mediators, including

Fig. 1. Roles of basophils as initiator of chronic allergic inflammation. In antigen-sensitized mice, circulating basophils are armed with antigen-specific IgE. After administration of
antigens into ear skin, a small number of basophils infiltrate into skin lesions and activated by antigens, leading to the release of a variety of mediators. Cytokines and other
mediators produced by activated basophils acts on skin-resident cells, including fibroblasts, endothelial cells, and ILCs. Stimulated skin-resident cells secrete substantial amount of
chemokines, promoting the migration of inflammatory cells, including neutrophils, eosinophils, monocytes and basophils. On the other hand, basophil-derived serine proteases
such as mMCP-11 act on serum proteins to generate chemotactic factors, leading to the recruitment of inflammatory cells. Thus basophil-derived inflammatory mediators induce
further recruitment of inflammatory cells, leading to chronic allergic inflammation.
384 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391
cytokines, chemokines, and proteases. Basophil-derived mediators
may act on skin-resident cells (fibroblasts, endothelial cells, and
others), leading to the recruitment of large number of inflammatory
cells. Basophil-derived proteases generate chemotactic factors by
acting on serum proteins, which can induce further basophil infil-
tration, as described in a later section. Thus, the infiltration of small
numbers of basophils leads to the aggravation of inflammation.
Basophils are required to migrate from blood to tissue, and therefore
basophil-dependent inflammation may show a delayed onset, in
contrast to acute-onset mast cell-dependent inflammation.
Basophils have been shown to play essential roles in IgE-
dependent skin allergy models other than IgE-CAI.15,16 Likewise, in
the course of repeated parasitic infections, IgE-armed basophils
infiltrate into sites of infection and play key roles in generating pro-
tective immunity against parasites in an IgE-dependent manner.17,18
IgE-dependent airway inflammation e rhinitis and asthma
In addition to skin inflammation, basophils contribute to several
models of IgE-dependent airway inflammation. Recent reports
have shown that depletion of basophils improves rhinitis symp-
toms in models of allergic rhinitis.19,20 In one model, mast cells are
also crucial for the development of allergic rhinitis,21,22 and it is
assumed that sequential engagement of mast cells and basophils is
important to elicit nasal immune responses.20 Allergen exposure
stimulates mast cells in nasal mucosa to release histamine, which
acts on the histamine H4 receptor on basophils, leading to migra-
tion of basophils into nasal tissues. Activated basophils in nasal
tissues release various mediators to induce both early- and late-
phase nasal reactions. In contrast to the allergic rhinitis model,
the role of basophils remains ill-defined in the IgE-dependent
allergic asthma model. One report indicated that mast cells, but
not basophils, are essential for the development of airway inflam-
mation in allergic asthma,13 whereas other reports have shown the
importance of basophils in airway inflammation and Th2 re-
sponses.23,24 These reports suggest that the relative importance of
basophils and mast cells in allergic asthma differs depending on
experimental conditions. Because basophils play crucial roles in
delayed-onset responses in IgE-CAI, it can be postulated that ba-
sophils may also play important roles in asthma models using
chronic allergen challenge.
Human allergic disorders
Whether basophils play crucial roles in human allergic disorders
remains unclear. However, recent clinical experiences with anti-IgE
antibody therapies (e.g., Omalizumab) provide some evidence of
their role in human diseases. Omalizumab binds to the FcεRI-
binding region of IgE, thus preventing interactions between soluble
IgE and FcεRI on basophils and mast cells. Downregulation of FcεRI
expression on basophils occurs within 2 weeks, whereas that on
mast cells typically occurs after 8 weeks.25,26 Therefore, it is ex-
pected that the therapeutic effects of omalizumab in basophil-
mediated allergic reactions can be observed as early as 1e2 weeks.
Chronic idiopathic urticaria (CIU) is defined as itchy hives that
last for at least 6 weeks and that have no apparent external trigger.
Although H1-antihistamines are widely prescribed for the initial
treatment of patients with CIU, the majority of patients do not
respond to these drugs, even at the maximum licensed dose.27
Recently, the administration of omalizumab has been shown to
diminish the clinical symptoms of CIU in phase 3 clinical trials, and
omalizumab is approved by the US Food and Drug Administration
(FDA) and European Medicines Agency (EMA) as a novel drug for
patients with CIU.28,29 Of note, the therapeutic effects of omalizu-
mab on patients with CIU can be observed within 1 week, sug-
gesting the involvement of basophils in the pathogenesis of CIU.28
Several observations support the role of basophils in CIU.30
Patients with CIU present blood basopenia, which is believed to
be the result of basophil migration into skin lesions. Consistent
with this, a recent report has shown that basopenia is significantly
ameliorated with omalizumab treatment.31 Furthermore, basophils
in patients with CIU show paradoxical suppression of FcεRI-medi-
ated histamine release, which reverses with disease remission.32 A
recent report showed that sera from patients with CIU suppressed
the activation of basophils from healthy donors, suggesting that
unknown suppressive factors are present in the sera of patients
with CIU.33 Taken together, results of these studies suggest that IgE
and basophils play essential roles in the pathogenesis of chronic
urticaria.
In contrast to CIU, contribution of basophils in other IgE-
mediated human allergic disorders including allergic rhinitis and
asthma remain poorly understood, although some evidences sug-
gest the role of basophils in these diseases.7,34,35
IgE-independent allergic inflammation
Basophils are also crucial in IgE-independent allergic inflam-
mation in mouse models, including asthma induced by allergenic
proteases,36,37 irritant contact dermatitis,38 atopic dermatitis (AD)-
like skin inflammation,39e41 and eosinophilic esophagitis (EoE)42,43
(Fig. 2). Basophils respond to a variety of innate immune-related
stimuli other than IgE with antigen stimulation.44 IL-3, a key
cytokine for basophil survival, induces IL-4 production in basophils
through interaction with the Fc receptor common g-chain (FcRg)
which is constitutively associated with the IL-3 receptor.45 IL-18
and IL-33, members of the IL-1 family of cytokines, also induce
IL-4 production in basophils.46 Toll-like receptor (TLR) ligands,
including lipopolysaccharide (LPS) and peptidoglycans (PGNs),
induce IL-4 production by basophils in the presence of IL-3.47,48
Several allergenic proteases such as papain and house dust mite-
derived proteases induce activation of basophils.49,50 A recent
report showed that extracellular ATP can also modulate basophil
activation.51
Recent findings indicate that basophils have two distinct sub-
populations depending on cytokine milieu, namely thymic stro-
mal lymphopoietin (TSLP)-elicited basophils and IL-3-elicited ba-
sophils.52 TSLP-elicited basophils show higher expression of
receptors for IL-3, IL-18, and IL-33, leading to their greater capacity
to release IL-4 in response to these cytokines, compared to IL-3-
elicited basophils. In contrast, TSLP-elicited basophils exhibit less
capacity to degranulate upon antigen and IgE stimulation. These
results suggest that TSLP-elicited basophils may play roles in IgE-
independent basophil activation. Indeed, TSLP plays key roles in
most of the IgE-independent allergic reactions mediated by
basophils.39e43
TSLP is reported to be highly expressed in keratinocytes from
patients with AD, and polymorphisms in TSLP are directly associ-
ated with AD.53,54 TSLP upregulation induced by a transgene spe-
cifically expressed in skin or repeated application of a chemical can
trigger AD-like skin inflammation in mice.55e57 In some TSLP-
dependent AD models, depletion of basophils results in the
amelioration of skin inflammation, suggesting the contribution of
TSLP-elicited basophils in these models.39e41
Gain-of-function polymorphisms in TSLP are also associated
with EoE, a food allergy-associated inflammatory disease strongly
associated with AD.58,59 Mouse models of EoE are established by
sensitization with food allergens in barrier-disrupted skin lesions,
followed by oral allergen challenge.42,43 Development of EoE in
these models is dependent on basophils and TSLP, and basophil
infiltrate is detected in esophageal lesions of mice and humans.42,43
Recent study demonstrated the significance of the IL-33-basophil
axis in this model.43 Depletion of basophils abolished the
 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391 385

Fig. 2. Involvement of basophils in IgE-dependent and IgE-independent allergic inflammation. Basophils are involved in both IgE-dependent and -independent allergic inflam-
mation. In IgE-dependent allergic inflammation, basophils are activated by antigen and IgE stimulation, causing degranulation and secretion of cytokines. Basophil-derived me-
diators induce the recruitment of other inflammatory cells, leading to the chronic allergic inflammation in antigen-challenged sites. IgE-independent allergic inflammation
mediated by basophils is mostly associated with TSLP. TSLP-elicited basophils are activated by cytokine stimulation, such as IL-3, IL18, and IL-33, leading to the secretion of IL-4.
Basophil-derived IL-4 induces the recruitment of inflammatory cells including eosinophils to the site of inflammation.

development of EoE, and EoE was recovered by adoptive transfer of
basophils from WT but not IL-33 receptor-deficient mice. Moreover,
IL-33 receptor expression is increased in esophagi of patients with
EoE.43 Based on these results, it can be postulated that TSLP-elicited
basophils infiltrate the esophagus and that basophils activated by
IL-33 and other stimuli initiate esophageal inflammation.
The significance of basophils and TSLP was also demonstrated in
food allergy models induced by epicutaneous sensitization with
allergens.40,60,61 TSLP and basophils play key roles in allergen-
specific IgE production during the sensitization phase, while mast
cells are important for the development of food allergy after chal-
lenge. Of note, the significance of TSLP receptors on dendritic cells
(DCs) has been demonstrated in one model, which suggests that
basophils and DCs work together to induce Th2 cells and IgE pro-
duction,61 as further discussed in later sections.
induces the expression of adhesion molecules such as vascular cell
adhesion molecule-1 (VCAM-1) in endothelial cells, which facili-
tates transmigration of eosinophils into inflammatory sites.16
Indeed, basophil-specific IL-4-deficient mice showed impaired in-
duction of VCAM-1 expression on endothelial cells and reduced
infiltration of eosinophils in skin lesion. In a papain-induced airway
inflammation model, basophil-derived IL-4 stimulates lung-
resident group 2 innate lymphoid cells (ILC2s), leading to the
secretion of larger amounts of IL-5, IL-13, and CCL11, thus inducing
the migration of eosinophils.36 Mice that specifically lack basophil-
derived IL-4 showed reduced secretion of cytokines in ILC2s and
impaired recruitment of eosinophils in lungs. Another group has
reported similar findings in an allergic skin inflammation model, in
which basophil-derived IL-4 induces the activation of skin-resident
ILC2s, thus promoting eosinophil migration into skin lesions.41

Basophil-derived effector molecules inducing allergic
inflammation
Although it is now widely appreciated that basophils contribute
to several mouse allergy models62,63 as described above, it has
remained unclear how basophils induce inflammation after acti-
vation. Recently, several studies shed some light on this issue. In
this section, we will focus on the effects of basophil-derived cyto-
kines, proteases, and other mediators on allergic inflammation.
Cytokines and chemokines
Role of basophil-derived IL-4 in allergic inflammation
Both mouse and human basophils are known to produce large
quantities of IL-4 in response to various stimuli. Roles of basophil-
derived IL-4 in allergic inflammation have been extensively studied
in recent years. Several lines of evidence indicate that basophil-
derived IL-4 acts on a variety of cell types to induce eosinophil
infiltration (Fig. 3). Indeed, basophil depletion leads to reduced
eosinophil recruitment to the site of inflammation in several allergy
models.16,36,38 In a co-culture system, basophil-derived IL-4 and
TNF-a stimulate fibroblasts to secrete eotaxin-1 (CCL11) and
RANTES (CCL5), causing the migration of eosinophils.38 In an IgE-
dependent skin inflammation model, basophil-derived IL-4
Role of other cytokines/chemokines derived from basophils
Besides IL-4, basophils from mice and humans produce various
cytokines and chemokines such as IL-6, IL-13, TNF-a, MIP-1a
(CCL3), and MIP-1b (CCL4).64 Basophil-derived IL-6 was recently
reported to be important for Th17 cell differentiation and humoral
memory responses,65,66 but further investigation is required to
define the significance of basophil-derived IL-6 in these responses.
Roles of other cytokines/chemokines in allergic reactions remain
largely unclear. A recent report suggested the contribution of
basophil-derived chemokines to tumor rejection.67 During the
rejection of melanoma tumors, depletion of regulatory T cells (Treg)
induces infiltration of basophils into tumors, which promotes CD8þ
T cell recruitment by basophil-derived CCL3 and CCL4, resulting in
efficient rejection of tumors. In addition to the cytokines
mentioned above, basophils can also produce amphiregulin, an
epidermal growth factor (EGF)-like cytokine, upon stimulation with
IL-3 produced by T cells.68 Basophil-derived amphiregulin is a key
participant in UVB irradiation-induced immune suppression by
enhancing the suppressive function of Treg cells.69
Effects of basophil-derived proteases on allergic inflammation
Both basophils and mast cells store serine proteases in their
granules and release them in response to various stimuli.
386 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391

Fig. 3. Versatile roles of basophil-derived IL-4 in allergic inflammation. Basophils can produce large amount of IL-4 in response to a variety of stimuli. In the early phase of
inflammation, basophil-derived IL-4 acts on skin-resident cells, including fibroblasts, endothelial cells, and ILCs, leading to the accumulation of eosinophils to the site of inflam-
mation. In the later phase of inflammation, basophil-derived IL-4 acts on inflammatory monocytes, leading to the differentiation into M2 macrophages. M2 macrophages promote
either resolution of allergic inflammation or protective immunity against helminthic parasites.

Importantly, recent studies have revealed that basophils and mast
cells in mice possess different serine proteases. We and other
groups have found that basophils rather than mast cells preferen-
tially express mouse mast cell protease 11 (mMCP-11) and mMCP-8,
while mMCP-6 and mMCP-7 are selectively expressed by mast
cells.70,71 The roles of mast cell-selective mMCP-6 and mMCP-7
have been extensively studied, and these proteases play signifi-
cant roles in protection against bacterial infections and the devel-
opment of inflammatory diseases. In contrast, the physiological
significance of basophil-selective mMCP-8 and mMCP-11 has
remained elusive until recently.
We found basophil-derived tryptase mMCP-11 plays crucial
roles in IgE-CAI responses72 (Fig. 4). mMCP-11-deficient mice
showed an ameliorated IgE-CAI response, with reduction in ear
swelling, microvascular permeability, and infiltration of leuko-
cytes, including eosinophils, neutrophils, and macrophages. In
addition, injection of recombinant mMCP-11 protein into mouse
ears induced cutaneous ear swelling with increased microvas-
cular permeability, and three consecutive injections of recombi-
nant protein induced cellular infiltration.72,73 Of note, mMCP-11
also induces leukocyte recruitment in a transwell migration
assay in vitro. Based on observations that this leukocyte migration
requires serum in culture media and that this migration activity
in response to mMCP-11 is dependent on protease activity,
mMCP-11 appears to cleave serum proteins, and proteolytic
products induce the migration of leukocytes, including basophils.
Inhibitor experiment further revealed that mMCP-11-elicited
leukocyte migration is dependent on G protein-coupled re-
ceptors (GPCRs). These findings indicate that mMCP-11, which is
released from basophils upon degranulation, promotes further
migration of basophils, leading to further release of mMCP-11 in
affected tissues.
Our recent report determined the function of mMCP-8 using
recombinant proteins74 (Fig. 4). Similar to mMCP-11, administration
of mMCP-8 into mouse ears induced ear swelling with increased
microvascular permeability and leukocyte infiltration in a protease
activity-dependent manner. However, unlike mMCP-11, mMCP-8
did not possess chemotactic activity in vitro, but rather induced
chemokine expression in skin-resident cells to induce leukocyte
infiltration. Thus, basophil-derived serine protease mMCP-8 and
mMCP-11 cooperatively induce allergic inflammation by promoting
increased microvascular permeability and leukocyte infiltration
through different mechanisms.
Effects of other mediators e histamine, PAF and lipid mediators
Histamine is the major chemical mediator stored in granules of
basophils. Histamine release from basophils is widely measured in
clinical tests for food allergies.75 However, the significance of his-
tamine released from basophils remains ill defined. Indeed, mast
cells and histamines play crucial roles in IgE-induced systemic
anaphylaxis, whereas basophils are dispensable for this reaction.76
In contrast, basophils play crucial roles in IgG-induced anaphylaxis
by releasing platelet-activating factor (PAF). However, following
studies also demonstrated the significance of neutrophils and
macrophages in IgG-induced anaphylaxis under different experi-
mental conditions,77,78 indicating that the relative contribution of
basophils, neutrophils, and macrophages in IgG-dependent
anaphylaxis can differ depending on experimental conditions. A
recent study indicates that the IgG subclass and its binding capacity
to Fcg receptors determine the contribution of basophils, neutro-
phils, and macrophages to IgG-induced anaphylaxis.79
Eicosanoids, lipid mediators generated from arachidonic acids,
are also released from basophils upon stimulation. Basophils have
 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391 387

Fig. 4. Basophil-derived proteases induce infiltration of inflammatory cells. Basophils release serine proteases including mMCP-8 and mMCP-11 upon degranulation. mMCP-11 acts
on serum proteins and proteolytic products of serum proteins induce the infiltration of other inflammatory cells in a GPCR-dependent manner. Of note, mMCP-11 induces the
infiltration of basophils, leading to the further secretion of serine proteases from activated basophils. In contrast, mMCP-8 induces the up-regulation of chemokine production,
possibly through acting on cells present in skin. Thus, basophil-derived serine proteases induce accumulation of inflammatory cells.

long been considered to release a much narrower range of eicosa-
noids, compared to mast cells.80 However, our recent study
revealed that basophils can produce 5-lipoxygenase (5-LOX) me-
tabolites and cyclooxygenase (COX) metabolites upon stimula-
tion.81 Furthermore, the production of COX metabolites from mast
cells and basophils are differentially regulated by COX-1 and COX-2,
leading to the distinct time course of metabolite production,
namely early-phase after stimulation in mast cells while late-phase
after stimulation in basophils.81
Regulation of other immune cells by basophils
Recent studies have revealed that basophils contribute to im-
mune regulation through their interaction with other immune
cells, including T cells, B cells, monocytes and macrophages.44 Ba-
sophils play a role in the regulation of acquired immunity, espe-
cially in the induction of Th2 differentiation39,49,82e84 and
amplification of humoral memory responses.66,85 In addition,
basophil-derived IL-4 is involved in the induction of M2-type
macrophages, leading to the resolution of inflammation and pro-
tection immunity against parasites.12,18 In this section, we will focus
on the immune modulatory functions of basophils.
Regulation of T cells by basophils
Th2 cells are crucial for protective immunity against extracel-
lular parasites and in several allergic reactions.86 IL-4 is widely
recognized to play critical roles in the differentiation of naïve T cells
into Th2 cells. The cellular source of IL-4 responsible for initial Th2
differentiation has long been a matter of debate, because several
cell types, including natural killer T cells, T cells, mast cells, eosin-
ophils, and basophils, are known to be able to produce IL-4.
Basophils rapidly release large amounts of IL-4 in response to a
variety of stimuli, as described in previous sections. Additionally,
analyses using IL-4-green fluorescence protein (GFP) reporter mice
revealed that basophils are the major source of IL-4 during hel-
minth infections.87 Indeed, co-culture of naïve T cells with wild-
type (WT) basophils in the presence of DCs induces robust pro-
duction of IL-4 in T cells, while co-culture with IL-4-deficient ba-
sophils fails to do so.88,89 These results highlight the importance of
basophils as a provider of IL-4 for Th2 differentiation in vitro. The
role of basophils in Th2 differentiation through the provision of IL-4
was further supported in a Th2 differentiation model caused by
allergenic proteases such as papain.49 Basophils were transiently
recruited to draining lymph nodes 1 day before the peak of Th2
differentiation in response to subcutaneous injection of papain.49
Basophils were localized in the T cell zone of draining lymph
nodes and expressed IL-4 in response to papain stimulation.
Depletion of basophils abolished Th2 differentiation induced by
papain immunization. Therefore, it was assumed that DCs act as
antigen-presenting cells (APCs) to induce Th2 differentiation
whereas basophils function as accessory cells in providing IL-4 to T
cells (Fig. 5A).
Following reports from three independent groups demon-
strated, under different experimental conditions, that basophils,
rather than DCs, function as the critical APCs in driving Th2 differ-
entiation in distinct experimental conditions (Fig. 5B).82e84 In all
settings, basophils expressed both major histocompatibility com-
plex class II (MHC-II) and co-stimulatory molecules (CD80, CD86, or
CD40) necessary for APC function and could process and present
antigens to naïve T cells, leading to Th2 cell differentiation. Deple-
tion of basophils using anti-FcεRI antibody abolished Th2 differen-
tiation in vivo, whereas depletion of DCs using CD11c-DTR chimeric
mice did not affect Th2 differentiation in these models.82,83
388 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391
Fig. 5. Basophils play key roles in Th2 differentiation. A. Role of basophils as a provider of IL-4 necessary for Th2 differentiation. DCs serve as APCs to promote Th2 differentiation,
and basophils in the vicinity of T cells supply IL-4 to T cells. B. Role of basophils as APCs producing IL-4. Basophils express MHC-II and function as crucial APCs for Th2 differentiation.
C. Role of trogocytosis of peptide-MHC-II complexes from DCs to basophils. Basophils acquire peptide-MHC-II complexes from DCs in cell contact-dependent manner, and peptide-
MHC-II-dressed basophils function as APCs to drive Th2 differentiation.
Furthermore, mice in which MHC-II expression was restricted to
DCs did not show Th2 differentiation in vivo.82,83 Conversely,
adoptive transfer of antigen-pulsed basophils was found to be suf-
ficient for the initiation of Th2 responses.83,84 This paradigm shift
was greeted with great enthusiasm, but also with criticism.90 One
concern has been the method used for depletion of DCs and baso-
phils. A report suggested the possibility that radioresistant DCs may
have remained intact in the DC-depleted chimeric mice.91 Another
report argued that the basophil-depleting anti-FcεRI antibody may
also have ablated FcεRI-expressing inflammatory DCs.92 Indeed, the
crucial role of DCs in Th2 differentiation was demonstrated in
studies that followed,14,93e95 suggesting that the relative contribu-
tions of basophils and DCs to Th2 differentiation vary depending on
experimental conditions. Additionally, basophils show relatively
low levels of cathepsin S expression, raising concerns about baso-
phils' ability of process and present antigen.92 Thus, the significance
of MHC-II expression on basophils and the antigen presentation
capacity of basophils remain controversial.
One recent report showed that basophils efficiently induce Th2
differentiation in response to peptide antigen rather than protein
antigen.39 Basophils contribute to ovalbumin (OVA) peptide-
induced Th2 differentiation, but not OVA protein-induced Th2
differentiation. Basophils have low capacity to take up and process
antigens, and thus are unable to present antigens to T cells when
protein antigens are administered. In contrast, basophils can induce
T cell proliferation and Th2 differentiation when basophils and
naïve T cells are co-cultured in the presence of peptide antigens.
From these results, authors have concluded that properties of an-
tigens, such as proteins, peptides, and haptens, may determine the
relative contribution of basophils to Th2 differentiation.39
We hypothesized that the difference in the level of MHC-II
expression on basophils might determine the contribution of ba-
sophils to Th2 differentiation, and investigated MHC-II expression
on basophils in various experimental conditions.96 We clearly
detected basophil MHC-II expression under certain conditions.
Unexpectedly, MHC-II expression was detected only at the protein
level, but not at the transcription level, suggesting that basophils
acquire MHC-II molecules from MHC-II-expressing cells such as
DCs. Consistently, co-culture of basophils with DCs results in the
detection of DC-derived peptide-MHC-II complexes on basophils.
Transfer of peptide-MHC-II complexes from DCs to basophils was
accompanied by the transfer of plasma membrane patches, sug-
gesting the involvement of trogocytosis in this phenomenon.97,98
Trogocytosis of MHC-II from DCs to basophils appears to occur
in vivo, because MHC-II expression on basophils isolated from
draining lymph nodes was abolished in DC-specific MHC-II-defi-
cient mice during atopic dermatitis-like inflammation. Acquired
peptide-MHC-II complexes enable basophils to stimulate antigen-
specific T cells and induce IL-4 production in T cells. Thus, baso-
phils can function as Th2-driving APCs through trogocytosis-
mediated MHC-II acquisition from DCs (Fig. 5C). The relative
contribution of basophils to Th2 cell differentiation may depend on
the extent of MHC-II trogocytosis from DCs. This appears to
reconcile some discrepancies observed previous studies.
Regulation of B cells by basophils
Besides their roles in T cell differentiation, basophils have been
shown to contribute to the modulation of B cell memory responses
in mice and humans.66,85 Basophils produce large amounts of IL-4
in secondary immune responses after immunization.99 However,
the role of basophil-derived IL-4 in memory responses, especially
antibody production by B cells, has remained elusive until recently.
Denzel et al. showed that basophils play crucial roles in humoral
immune responses by producing IL-4 and IL-6, which induce a B
cell helper phenotype in CD4þ T cells and enhance B cell prolifer-
ation and antibody production.66 Basophils can efficiently capture
antigens after primary immunization via antigen-specific IgE and
high-affinity IgE receptors on basophils.66,100 Basophils are the
main source of IL-4 and IL-6 after challenge, as shown in previous
studies. Of note, basophil depletion abrogated the production of
antigen-specific IgG1 and IgG2a antibody after secondary antigen
challenge. The number of antigen-specific B cells also decreased
after depletion of basophils. Indeed, in vitro co-culture of activated
WT basophils, but not IL-6-deficient basophils, with activated CD4
T cells and B cells enhanced the proliferation of and antibody
 K. Miyake, H. Karasuyama / Allergology International 66 (2017) 382e391
production by B cells, suggesting the importance of basophil-
derived IL-6 in B cell help. Additionally, activated basophils
induce a B cell helper phenotype in CD4 T cells through IL-4, IL-6,
and CD40L expression. Furthermore, Denzel et al. demonstrated the
significance of basophils in a vaccination model using pneumo-
coccal surface protein A (PspA), a component of Streptococcus
pneumoniae. Basophil depletion decreased PspA-specific antibody
production and increased the occurrence of sepsis caused by
intratracheal infection with S. pneumoniae. Later studies revealed
that basophils in mice and humans support plasma cell survival in
the bone marrow and spleen and that this is partly dependent on
IL-4 and IL-6 produced by basophils.101,102 In addition, long-term
depletion of basophils after immunization reduced the number of
plasma cells in spleens.101
Another group discovered a B cell-stimulating function of ba-
sophils in response to IgD.85 Circulating basophils in humans
constitutively exhibit abundant surface IgD via unknown receptors
on their cell surface. Crosslinking of IgD using anti-IgD monoclonal
antibody induces calcium influx and the production of IL-4, IL-13,
soluble B cell-activating factor (BAFF), and membrane-bound a
proliferation-inducing ligand (APRIL), which are known to be B cell-
activating factors. Indeed, co-culture of IgD-activated basophils
with B cells induced the production of IgM, IgA, and IgG in vitro.
Furthermore, IgD stimulation of basophils induced the expression
of antimicrobial factors, including b-defensin 3 and cathelicidin.
Because IgD secreted from plasmablasts in the upper respiratory
mucosa reacts with respiratory bacteria, IgD-activated basophils
appear to play crucial roles in innate and adaptive immune pro-
tection from pathogens by producing anti-bacterial factors and
antibodies specific for pathogens.
Activation of basophils contributes to the production of autoan-
tibodies in a lupus-like nephritis model.103 Basophils are activated by
IgE-immune complexes and support the production of autoreactive
antibodies, leading to lupus-like nephritis. Furthermore, serum levels
of autoreactive IgE antibody and the expression of activation markers
on basophils are associated with disease activity in patients with
systemic lupus erythematosus (SLE), suggesting the involvement of
IgE and basophils in patients with SLE.103,104
Regulation of monocytes and macrophages by basophils
Our group discovered in an IgE-CAI model that basophil-derived
IL-4 dampens exacerbated inflammation by inducing the differen-
tiation of M2-like macrophages in later stages of inflammation
(Fig. 3).12 Macrophages show phenotypic plasticity in response to
various environmental stimuli such as classically activated M1
macrophages and alternatively activated M2 macrophages, which
mirror Th1 and Th2 polarization in T cells, respectively.105,106 M2
macrophages are generally assumed to play significant roles in
wound healing, tissue remodeling, parasite clearance, and resolu-
tion of excessive inflammation.105,106 However, the role of M2
macrophages in allergic inflammation remains controversial,
because some studies have shown that M2 macrophages promote
allergic responses, whereas others demonstrate suppressive effects
on allergic inflammation.107 In IgE-CAI responses, inflammatory
monocytes are recruited to skin lesions and differentiate into M2-
like macrophages in response to IL-4, which results in the sup-
pression of excess inflammation in allergic reactions. Based on
evidence that basophils are the major sources of IL-4 in skin lesions
in IgE-CAI and that basophil depletion impairs the generation of
M2-like macrophages, IL-4 secreted by activated basophils appears
to contribute to M2-like macrophage polarization. Thus, basophil-
derived IL-4 involves the termination of IgE-CAI by promoting M2
macrophage generation.
389
Recent reports indicate that M2 macrophage generation
induced by basophil-derived IL-4 plays key roles in a wide variety of
immune responses. We showed that M2 macrophages generated in
the skin are important for protection from the helminth Nippos-
trongylus brasiliensis (Nb). During secondary Nb infection, IgE-
armed basophils infiltrate skin infection sites and trap Nb larvae
in skin. Basophil-derived IL-4 promotes the generation of M2
macrophages, which leads to the retention and killing of larvae by
arginase-1.18 Additionally, a recent report showed that M2 macro-
phage generation in response to basophil-derived IL-4 contributes
to liver homeostasis after infection with Listeria monocytogenes
(Lm). Lm infection induces early cell death of liver-resident Kupffer
cells, resulting in anti-bacterial type 1 responses. Kupffer cell death
also induces secretion of IL-33 from hepatocytes, leading to IL-4
production by basophils and M2 macrophage generation from
monocytes. Differentiated M2 macrophages replace dead Kupffer
cells to maintain tissue homeostasis.108
Concluding remarks
Basophils have long been neglected in the immunology field
because of their similarities with mast cells and their rarity. How-
ever, recent advances in the development of analytical tools have
accelerated functional research on basophils. Basophils are now
accepted to play key roles in various types of IgE-mediated allergic
inflammation. Moreover, basophils have also been shown to play
crucial roles in TSLP-mediated and IgE-independent allergic
inflammation. Basophils have the potential to initiate and expand
inflammation through the production of specific cytokines and
proteases. Basophils can also induce Th2 differentiation in coop-
eration with DCs. In addition, basophils play significant roles in the
resolution of inflammation by inducing M2 macrophages.
Recent clinical experiences suggest the role of basophils in the
pathogenesis of several allergic disorders. Therefore, further
elucidation of the molecular mechanisms underlying basophil-
mediated allergic diseases will be the good help for the develop-
ment of novel therapeutic target for allergic diseases.
Acknowledgments
This work is supported by research grants from the Japanese
Ministry of Education, Culture, Sports, Science and Technology
(Grant number: 15H05786).
Conflict of interest
The authors have no conflict of interest to declare.
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