REVIEW
Mast cells: an expanding pathophysiological role from allergy
to other disorders
Preet Anand & Baldev Singh & Amteshwar Singh Jaggi &
Nirmal Singh
Received: 16 December 2011 /Accepted: 17 April 2012 /Published online: 6 May 2012
# Springer-Verlag 2012
Abstract The mast cells are multi-effector cells with wide
distribution in the different body parts and traditionally their
role has been well-defined in the development of IgE-
mediated hypersensitivity reactions including bronchial
asthma. Due to the availability of genetically modified mast
cell-deficient mice, the broadened pathophysiological role
of mast cells in diverse diseases has been revealed. Mast
cells exert different physiological and pathophysiological
roles by secreting their granular contents, including vasoac-
tive amines, cytokines and chemokines, and various pro-
teases, including tryptase and chymase. Furthermore, mast
cells also synthesize plasma membrane-derived lipid medi-
ators, including prostaglandins and leukotrienes, to produce
diverse biological actions. The present review discusses the
pathophysiological role of mast cells in different diseases,
including atherosclerosis, pulmonary hypertension,
ischemia-reperfusion injury, male infertility, autoimmune
disorders such as rheumatoid arthritis and multiple sclerosis,
bladder pain syndrome (interstitial cystitis), anxiety, Alz-
heimer’s disease, nociception, obesity and diabetes mellitus.
Keywords Mast cells . Male infertility . Cancer . Ischemia-
reperfusion injury . Irritable bowel disorder
Introduction
The mast cells were first described in 1876 by Paul Ehrlich,
who designated them as “Mastzelle”. Mast cells are long-
lived, highly granulated, FcεRI-bearing cells that are de-
rived from the hematopoietic stem cells and circulate as
immature progenitors and get matured in the tissues where
they enter (Galli and Tsai 2010). Mast cells are highly
granulated cells and these are partially or completely degra-
nulated by a wide range of immunological as well as non-
immunological stimuli. The granules of these inflammatory
cells contain histamine, heparin, serotonin, chemotactic fac-
tors and various proteases such as peroxidase, tryptase,
chymase, carboxidase, beta glucuronidase as primary medi-
ators (Schwartz and Austen 1980). Moreover, activation of
mast cells generates secondary mediators such as prosta-
glandins, leukotrienes, platelet activating factor (PAF) and
various cytokines, such as interleukin (IL)-1, IL-3, IL-4, IL-5,
IL-6, granulocyte macrophage colony stimulating factor (GM-
CSF), macrophage inflammatory protein (MIP)-1β, MIP-1α
and TNF-α (Plaut et al. 1989). Due to synthesis and release of
diverse types of inflammatory mediators, mast cells may
produce pathophysiological changes in various organs, lead-
ing to the development of different diseases (Fig. 1). Mature
mast cells show a strong species and organ-specific heteroge-
neity related to morphology and function. Their functional
reactivity is also critically dependent on the microenviron-
ment. Thus, according to local tissue conditions, mast cells
adapt and release mediators according to tissue conditions
(Lowman et al. 1988). Mast cells are composed of two phe-
notypes: mucosal mast cells, which contain tryptase but not
chymase, and connective tissue type mast cells, which contain
both proteases (Galli 1990).
Mast cells are part of the innate immune system and
participate in the first line of defense against pathogens such
P. Anand : B. Singh
Department of Chemistry, Punjabi University,
Patiala 147002, India
A. S. Jaggi :N. Singh (*)
Department of Pharmaceutical Sciences and Drug Research,
Punjabi University,
Patiala 147002, India
e-mail: nirmal_puru@rediffmail.com
Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385:657–670
DOI 10.1007/s00210-012-0757-8
as bacteria and parasites, and release their granules after
activation of mast cell receptors. Traditionally, mast cells
are considered as major effectors in IgE-associated immedi-
ate hypersensitivity and in allergic responses such as asth-
ma. However, recent research has broadened the functions
of mast cells and their pathophysiological roles in various
diverse diseases have been recognized. The findings related
to the role of mast cells in different diseases have been due
to the availability of mast cell-deficient mouse models, includ-
ing KitW/Wv (WBB6F1-KitW/W
v or W/W-v) (Kitamura et al.
1978), KitW-sh/W-sh (Lyon and Glenister 1982) and SJL-KitW/
W-v (Sayed et al. 2011). KitW/Wvmice have a mutation in the c-
kit gene that encodes the transmembrane receptor with intrin-
sic tyrosine kinase activity for stem cell factor (SCF). SCF is a
major migration, proliferation, maturation and survival factor,
and is important for efficient mast cell development. These
mice have a defect in the cell surface expression of kit
(CD117) and are severely mast cell-deficient (∼1% of nor-
mal). But their major limitation is that they are sterile. The
KitW-sh/W-sh mice are having an inverted segment of chromo-
some 5 in the regulatory element of the c-kit gene, which
reduces its expression in the form of reduced CD117 (kit) on
the surface of mast cells. However, these mice are fertile
compared with KitW/W-v mice. SJL-KitW/W-v mice are mast
cell deficient in all the tissues but have relatively normal
thymic T cell compartments. These animals have been created
by transferring the c-KitW/Wv mutation on the SJL back-
ground, a strain that is susceptible to remitting relapsing
multiple sclerosis (Sayed et al. 2011).
The availability of different mast cells stabilizers such as
sodium cromoglycate, nedocromil sodium and ketotifen has
also helped to identify the role of mast cells in the patho-
physiology of different diseases. Sodium cromoglycate is
widely employed as mast cell stabilizer and clinically
employed for the management of bronchial asthma (Alton
and Norris 1996; Parnham 1996), allergic rhinitis (Pedinoff
1996) and allergic conjunctivitis. There have been several
reports documenting the strain-specific variability in
number of mast cells and variation in response to distinct
activation signals and inhibitors including sodium cromo-
glycate in mice (Johnson et al. 1991; Yong et al. 1994; Bebo
et al. 1996; Sayed et al. 2011). Accordingly, sodium cromo-
glycate may not act as a mast cell stabilizer in some mast
cell populations due to species-related heterogeneity of mast
cells. This may be responsible for variability of response
observed in different studies especially using different
strains of mice. The present review discusses the pathophys-
iological role of mast cells in different diseases, including
atherosclerosis, pulmonary hypertension, ischemia-
reperfusion injury, male infertility, nociception, anxiety,
Alzheimer’s disease, auto-immune diseases, obesity, and
diabetes.
Atherosclerosis
There have been extensive studies suggesting the pro-
atherogenic potential of mast cells (Bot and Biessen 2011).
Mast cells have been localized in the vessel walls, particu-
larly in perivascular tissue which may point to their role in
pathogeneses of atherosclerosis. Earlier clinical studies
demonstrated the abundant presence of mast cells in the
intima and perivascular tissue (adventitia) of atherosclerotic
plaques in the diseased coronary arteries (Kaartinen et al.
1994; Kovanen et al. 1995; Jeziorska et al. 1997) and the
increase in numbers was correlated with the disease progres-
sion. Furthermore, the clinical studies also demonstrated the
co-localization of mast cells with intraplaque neovessels,
suggesting the role of mast cells in intraplaque hemorrhage
and plaque destabilization (Kaartinen et al. 1996; Lappalainen
et al. 2004). In advanced atherosclerotic lesion, adventitial
mast cells have been shown to co-localize with nerve fibers
and thereby suggesting a correlation between neuronal factors,
mast cells and atherosclerosis. It has been proposed that
neurogenic stimulation might degranulate mast cells in peri-
vascular coronary artery tissue and release pro-inflammatory
Fig. 1 The possible inter-
linked mechanisms involved in
mast cells mediated pathophys-
iological changes in different
diseases. Ang angiotensin,
MMP matrix metalloproteinase,
ECM extracellular matrix, NO
nitric oxide, 5-HT 5-hydroxy
tryptamine, RASF rheumatoid
arthritis synovial fibroblasts,
JNK c-Jun N-terminal kinase,
WBC white blood cells
658 Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385:657–670
mediators that may be responsible for plaque destabilization
(Laine et al. 2000). The clinical data has also shown increased
levels of IgE (mast cell activator) in dyslipidemia (Kovanen et
al. 1998) and histamine (biomarker of mast cells) in coronary
artery disease patients (Clejan et al. 2002).
Along with clinical reports, experimental studies have
also documented the pro-atherogenic role of mast cells.
Earlier studies showed that mast cell-derived heparin binds
to low-density lipoprotein (LDL) particles, implying that
mast cell granules may help in retaining LDL in the blood
vessels (Kokkonen and Kovanen 1987a). Furthermore in the
in vitro system, stimulation of mast cells has also been
shown to cause cholesterol accumulation in macrophages
by an increased uptake of LDL molecules (Kokkonen and
Kovanen 1987b). On the other hand, the oxidized LDL
molecules have been shown to induce mast cell degranu-
lation and leukocyte adhesion, which may further exacer-
bate the atherosclerotic process (Paananen and Kovanen
1994).
In more recent studies, it was conclusively demonstrated
that systemic mast cell activation aggravates the atheroscle-
rotic lesion formation in apoE-deficient mice (Tang et al.
2009) and mast cell stabilizers prevent this effect. Further-
more, it has also been shown that mast cell activation in
perivascular tissue of advanced atherosclerosis in apoE-
deficient mice leads to plaque instability, indicated by
plaque hemorrhage, apoptosis and leukocyte recruitment
(Guo et al. 2009; Bot et al. 2011). Activation of mast cells
is associated with the release and secretion of proteolytic
enzymes, including chymase, tryptase, and metalloprotei-
nases, that may degrade the various components of pericel-
lular and extracellular matrices, including collagen (main
protein of the fibrous cap of atherosclerotic plaque) to
render plaque destabilization (Bot et al. 2011; Czyzewska-
Buczyńska and Witkiewicz 2011). In mast cell-deficient W-
sh/W-sh mice, the reduced atherogenesis in the aorta has been
demonstrated (Sun et al. 2007). The key role of mast cell-
derived pro-inflammatory cytokines such as IL-6, interferon
(IFN)-γ, TNF-α induced up-regulation adhesion molecules
such as VCAM-1, intercellular adhesion molecule-1
(ICAM-1), and P- and E-selectin in atherosclerotic progres-
sion has been defined (Sun et al. 2007). It has been sug-
gested that mast cell-dependent lipoprotein modification,
lipoprotein-mediated mast cell activation and subsequent
leukocyte recruitment may be a vicious cascade by which
mast cells contribute to the progression of atherosclerosis.
The studies have suggested that identifying the endogenous
triggers of mast cell degranulation followed by their block-
ade may attenuate the progression of cardiovascular dis-
eases. The endogenous triggers particularly related to
atherosclerosis include oxidized LDL molecules (Kelley et
al. 2006), microbes residing in the plaque such as Chlamyd-
ia pneumoniae (Hauer et al. 2006), C3a and C5a as
complementary factors (Oksjoki et al. 2007), and neuropep-
tides such as neuropeptide P (Bot et al. 2010).
Pulmonary hypertension
There has been evidence documenting the critical role of
mast cells in the development of pulmonary hypertension as
a consequence of tissue remodeling (Hoffmann et al. 2011).
Mast cell inhibition attenuates pulmonary vascular remodel-
ing in pulmonary hypertension in rats and a lower chymase
activity correlates with more favorable hemodynamics and
pulmonary vascular remodeling (Bartelds et al. 2012). Ear-
lier studies demonstrated an increased number of mast cells
in the primary plexogenic pulmonary arteriopathy (Heath
and Yacoub 1991), pulmonary hypertension (Mitani et al.
1999) and congenital heart diseases associated with early
pulmonary vascular diseases (Hamada et al. 1999). Further-
more, it has also been described that a large number of mast
cells accumulate around the vessels in monocrotaline-
induced pulmonary hypertension (Miyata et al. 2000), par-
ticularly around the pulmonary vessels in rats with severe
pulmonary hypertension. A recent finding has demonstrated
that the majority of the perivascular mast cells are in a
degranulated state in an experimental model of pulmonary
hypertension (Dahal et al. 2011).
Banasova et al. (2008) demonstrated that mast cell de-
granulation plays an important role in initiating hypoxic
pulmonary vascular remodeling as administration of sodium
cromoglycate in an early phase of isobaric hypoxia effec-
tively prevented the development of pulmonary hyperten-
sion. However, delayed administration of cromoglycate was
not found to be effective in preventing hypertension in
pulmonary blood vessels. Therefore, it may be deduced that
an inhibition of mast cell degranulation impairs the devel-
opment but does not affect the established pulmonary hy-
pertension in rats. On the contrary, it has been shown that
prevention of mast cell degranulation by disodium cromo-
glycate delays the regression of hypoxic pulmonary hyper-
tension following chronic hypoxia in rats, suggesting that
mast cell degranulation plays a role in the regression of
pulmonary hypertension during the early phase of recovery
from chronic hypoxia (Maxová et al. 2010).
The products of mast cell degranulation, i.e., serotonin,
cytokines (IL-6, IL-13), chymase, and matrix metalloprotei-
nase (MMP 13), are known to act as important mediators in
the pathogenesis of pulmonary hypertension and pulmonary
vascular remodeling (Mitani et al. 1999; Hassoun et al.
2009). A clinical study has documented the presence of
chymase positive mast cells in vascular lesions with intimal
fibrosis in pulmonary hypertensive patients suggesting the
role of chymase in the fibrous changes of the neointima
(Mitani et al. 1999). It has been proposed that chymase is
Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385:657–670 659
involved in pulmonary hypertension indirectly by convert-
ing angiotensin I to angiotensin II, whose role in pulmonary
hypertension and its vascular changes in chronically hypox-
ic rats has been very well described (Morrell et al. 1995).
The serotonin also plays a key role in pulmonary arterial
vasoconstriction and smooth muscle cell proliferation
(MacLean and Dempsie 2009).
The production and secretion of mast cell mediators is
regulated by mast cell growth factor, also referred to as stem
cell factor or kit ligand (Bischoff and Dahinden 1992). The
cytokines are the representative ligands of the kit tyrosine
kinase receptor (clustered as CD117) and kit is employed as
a marker for bone marrow-derived hemopoietic stem cells
and mast cells. However, kit expression is downregulated on
maturation of all hemopoietic lineages, except mast cells
that retain high levels of expression (Miettinen and Lasota
2005). The critical role of kit in the development of pulmo-
nary hypertension has been reported. It has been described
that kit helps in promoting perivascular mast cell accumu-
lation and degranulation in the lungs (Dahal et al. 2011). A
recent study has shown that kit-positive cells accumulate in
remodeled vessels of idiopathic pulmonary arterial hyper-
tension (Montani et al. 2011). Tyrosine kinase inhibitors
(imatinib) has been shown to reduce perivascular accumu-
lation of kit+ cells in pulmonary arteries of mice exposed to
chronic hypoxia along with improvement in pulmonary
vascular remodeling (Gambaryan et al. 2010; 2011).
Ischemia-reperfusion injury
Mast cells are localized in the heart as resident cardiac mast
cells mainly in perivascular areas along small veins and
capillaries (Sperr et al. 1994). The preliminary suggestion
given by Jolly et al. (1982) that cardiac mast cells may be
associated with ischemia-reperfusion-induced myocardial
injury was well supported by other reports (Keller et al.
1988). It has also been reported that mast cells accumulate
in the heart after ischemia and reperfusion (Frangogiannis et
al. 1998). The studies from our laboratory as well from
others have reported that the stabilization of resident cardiac
mast cells with ketotifen, disodium cromoglycate and lodox-
amide provide myocardial protection against ischemia-
reperfusion injury (Parikh and Singh 1998; Jaggi et al.
2007). The mast cell degranulation-induced release and syn-
thesis of cytotoxic mediators may produce myocardial injury
(Singh and Saini 2003). Furthermore, the mast cell-derived
mediators may also cause recruitment of leukocytes (Kubes
and Granger 1996) and inflammatory reactions may contrib-
ute significantly in causing myocardial injury (Frangogiannis
et al. 2002; Ren et al. 2003). A recent study has suggested that
extravasated plasmin mediates neutrophil recruitment via ac-
tivation of perivascular mast cells and secondary generation of
lipid mediators. The plasmin inhibitors such as tranexamic
acid and ε-aminocaproic acid interfere with this inflammatory
cascade and effectively prevent postischemic neutrophil
responses as well as remodeling events within the vessel wall
(Reichel et al. 2011).
The studies have shown that perivascularly located cere-
bral mast cells participate in acute blood–brain barrier dis-
ruption and expansive brain edema in an experimental
transient cerebral ischemia (Strbian et al. 2009). Our own
study has shown the critical role of cerebral mast cells in
mediating neuronal damage in an experimental model of
ischemia (Rehni et al. 2008). Mast cells release cytotoxic
mediators that act on the basal membrane to promote blood–
brain barrier damage, brain edema, prolonged extravasation
and hemorrhage (Lindsberg et al. 2010). A recent study has
shown that activated mast cells show secretion of gelatinase-
positive granules, suggesting that cerebral mast cells regu-
late activation of proteolytic microvascular gelatinase to
participate in blood–brain barrier disruption following tran-
sient cerebral ischemia (Mattila et al. 2011). The studies
have also suggested the role of mast cells in ischemia-
reperfusion-induced intestinal injury (Sand et al. 2008).
Administration of ketotifen and sodium cromogycate is
shown to decrease the multi-organ injury induced by intestinal
ischemia reperfusion and increase the survival rates (Hei et al.
2008). Mast cells secrete CXC chemokines and promote
leukocyte rolling and adhesion in the colonic microvascular
bed that in turn initiates cascade of inflammatory reactions to
promote intestinal injury (Santen et al. 2008).
Male infertility
There have been a number of studies documenting an in-
creased number of mast cells in the testes, epididymis and
seminal fluid of males exhibiting infertility with oligosper-
mia or/and azoospermia (El-Karaksy et al. 2007; Haidl et al.
2011; Menzies et al. 2011) along with beneficial effects of
treatment with mast cell blockers on impaired male fertility
(Hibi et al. 2002). A mast cell blocker such as ketotifen has
been documented to improve semen parameters, chromatin
integrity and pregnancy rates as in infertile males following
post-varicocelectomy (Azadi et al. 2011) and in male
patients with leukocytospermia and unexplained infertility
(Oliva and Multigner 2006). Using the testicular biopsies of
patients with infertility, a positive relationship was estab-
lished between expression of iNOS score and mast cell
accumulation, suggesting the critical role of mast cell-
derived nitric oxide in producing damage of the germ cell
and eventually infertility (Sezer et al. 2005). Mast cell-
derived mediators affect sperm funct