published: 30 January 2019
Frontiers in Endocrinology | www.frontiersin.org 1January 2019 | Volume 10 | Article 26
Case Western Reserve University,
Qilu Hospital of Shandong University,
Asahikawa Medical University, Japan
Johns Hopkins University,
This article was submitted to
a section of the journal
Frontiers in Endocrinology
Received: 23 October 2018
Accepted: 15 January 2019
Published: 30 January 2019
Tu L and Yang L (2019) IL-33 at the
Crossroads of Metabolic Disorders
Front. Endocrinol. 10:26.
IL-33 at the Crossroads of Metabolic
Disorders and Immunity
Lei Tu 1and Lijing Yang2
1Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology,
Wuhan, China, 2Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
As a cytokine in interleukin-1(IL-1) family, interleukin-33(IL-33) usually exists in the
cytoplasm and cell nucleus. When the cells are activated or damaged, IL-33 can be
secreted into extracellular and regulate the functions of various immune cells through
binding to its speciﬁc receptor suppression of tumorigenicity 2 (ST2). Except regulating
the function of immune cells including T cells, B cells, dendritic cells (DCs), macrophages,
mast cells, and innate lymphoid cells, IL-33 also plays an important role in metabolic
diseases and has received an increasing attention. This review summarizes the regulation
of IL-33 on different immune cells in lipid metabolism, which will help to understand
the pathology of abnormal lipid metabolic diseases, such as atherosclerosis and type
Keywords: IL-33, metabolism, diabetes, innate & adaptive immune response, ST2
IL-33, a new member of the IL-1 family, was discovered in 2005 (1) while its receptor ST2
containing intracellular domain Toll/IL-1R (TIR) was found in BALB/c-3t3 mouse ﬁbroblasts in
1989 (1,2). The receptor complex of IL-33 is composed of ST2 and interleukin-1 receptor accessory
protein (IL-1RAcP). IL-33 mediates its biological eﬀect through binding to its speciﬁc receptor ST2
(2,3), whereas the expression of ST2 is restricted and determines the cellular responsiveness to
IL-33 treatment (3).Two forms of ST2 have been demonstrated, a membrane-bound form (ST2L)
and a soluble form (sST2), the latter which prevents its signaling as the decoy receptor for IL-
33. IL-33 is mainly expressed in ﬁbroblasts, epithelial cells and endothelial cells, and especially
in high endothelial venules (HEV) (4). Indeed, as designated as an “alarmin,” IL-33 is usually
released after cell injury to alert the immune system and initiate repair processes. In a recent study,
islet mesenchymal-cell-derived IL-33 has been identiﬁed as an islet immunoregulatory feature
(5). As the receptor of IL-33, ST2 is expressed in many immune cells. IL-33 is a dual-function
cytokine. In the absence of inﬂammatory stimulation, IL-33 is located in the nucleus as a nuclear
factor. Once the cell is damaged and/or necrotic, IL-33 can be released from the nucleus and
then act as an endogenous “alarmin” (4). The activation signal produced by IL-33/ST2 pathway is
transmitted to the cell and a series of signal transmissions activate nuclear factor kappa-light-chain-
enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway to
regulate immune response (1,6). Under normal physiological condition, inﬂammation induced by
a dysregulated lipid metabolism is beneﬁt for the maintenance of homeostasis and is controlled to
avoid excessive damage to the host. However, if not properly controlled, the inﬂammatory response
will promote the excessive production of lipid metabolites, inﬂammatory cytokines and adhesion
molecules, which lead to acute or chronic diseases (7), such as obesity, non-alcoholic steatohepatitis
(NASH), atherosclerosis, and acute cardiovascular events. To date, an increasing body of evidence
has demonstrated that IL-33 plays a critical role in the lipid metabolism. This review highlights
Tu and Yang IL-33 Regulates Metabolic Disorders
the function of IL-33/ST2 axis on diﬀerent immune cells in the
IL-33/ST2L SIGNALING IN INNATE
IL-33 and ST2 have been shown to be expressed in human and
murine adipose tissue, and IL-33 expression is strongly correlated
with leptin expression in human adipose tissue (8). In addition,
administration of IL-33 increases browning of white adipose
tissue and energy expenditure in mice (9). These observations
show that a critical role of IL-33 played in the adipose tissues
Macrophages have functional plasticity in adipose tissue
inﬂammation, which can exhibit pro-inﬂammatory or anti-
inﬂammatory function. According to the phenotypes and
secreted cytokines, macrophages can be divided into two
categories named as classical activated macrophages (CAM,
M1 type) and alternatively activated macrophages (AAM, M2
type), respectively. CAM are generated in response to helper T1
cells (Th1 cells)-related cytokines, such as interferon-γ(IFN-γ)
and tumor necrosis factor-α(TNF-α), while AAM polarization
is linked to the helper T2 cells (Th2 cells)-related cytokines
(IL-4 and IL-13) (10). Previous studies showed that AAM
could attenuate adipose tissue inﬂammation and obesity-induced
insulin resistance (11–14). It has been showed that ST2 can
be detected on the cell surface of macrophages. IL-33 can
promote the expression of lipopolysaccharide (LPS) receptor
components such as myeloid diﬀerentiation factor 2 (MD2), toll-
like receptor (TLR) 4, soluble cluster of diﬀerentiation 14 (CD14)
and myeloid diﬀerentiation primary response gene 88 (Myd88),
which result in an enhanced inﬂammatory cytokine production
(15). However, IL-33 administration improves glucose tolerance,
which is associated with the accumulation of M2 macrophages in
adipose tissue of ob/ob mice that are the mutant mice to construct
the model of Type II diabetes (16). As the result of purine
metabolism disorder, gout is a very common metabolic disease
in human (17,18). Hyperlipidaemia is common in gout patients
including increased low-density lipoprotein (LDL) cholesterol
and decreased high-density lipoprotein (HDL) cholesterol (19).
The serum IL-33 expression is predominantly increased in gout
patients compared to healthy controls and positively correlated
with the expression of HDL, while negatively correlated with
LDL expression (20). It has been reported that the elevated
IL-33 level is considerably reduced in renal impairment when
compared with normal renal function in gout patients (20–22).
These data suggest that IL-33 may prevent the kidney injury
through regulating the lipid metabolism, which may be resulted
from the AAM polarization.
Although ST2 can be detected on the cell surface of
macrophages, IL-33/ST2 signaling cannot directly promote AAM
polarization. The involvement of IL-33/ST2 signaling in the
diﬀerentiation and activation of AAM is associated with type II
cytokines induction (23–25). A previous ﬁnding showed that a
population of cells expressing ST2 in adipose was potential to
produce large amounts of Th2 cytokines in response to IL-33
(26). Recent studies have named this population as group 2 innate
lymphoid cells (ILC2s), characterized by expressing ST2 receptor,
and secreting type 2 cytokines such as IL-5 and IL-13 in response
to IL-33 (27–30). In addition, soluble ST2 can prevent ILC2s from
IL-33 stimulation (31). Recent observation has shown that ILC2s
activation favors macrophages toward a protective AAM, which
lead to a reduced lipid storage and decrease gene expression
of lipid metabolism and adiposeness (32). Furthermore, it has
showed that IL-13Rα2 may act as a critical checkpoint in the
protective eﬀect of the IL-33/IL-13 axis in obesity (33). In
addition, IL-33 promotes βcell function through islet-resident
ILC2s that elicite retinoic acid (RA)-producing capacities in
macrophages and dendritic cells via the secretion of IL-13 and
colony-stimulating factor 2 (5). These data suggest that IL-33
plays a protective role in the adipose tissue inﬂammation through
regulating macrophage function, which is closely associated with
the activation of ILC2 to produce type 2 cytokine and IL-4Rα
IL-33/ST2L SIGNALING ON T CELL
As a subset of T cells, the regulatory T cells (Tregs) play a critical
role in suppressing autoimmune reactivity and have gained an
increasing attention in the autoimmune diseases (34). It is shown
that an impaired Tregs function is investigated in ST2 gene
knockout mice with streptozotocin-induced diabetes, where the
glycaemia and βcell loss are severe (35). Indeed, the exogenous
IL-33 treatment propagates Tregs expressing the ST2 on the
cellular surface, which suggests that the Tregs expansion induced
by IL-33 administration is likely to be the result of a direct eﬀect
of IL-33 on ST2L+Tregs (36,37). Besides, ST2+DCs stimulated
by IL-33 to secrete IL-2, which promotes the selective expansion
of ST2+Tregs vs. non-Tregs, are required for in vitro and in vivo
Tregs expansion (37,38). In the Th1/Th17-mediated allograft
rejection, IL-33 treatment can prevent allograft rejection through
increasing ST2 positive Tregs in mice (39). In the mouse model
of trinitrobenzene sulfonic acid (TNBS)-induced colitis, dextran
sulfate sodium (DSS)-induced colitis or T cell adoptive transfer
induced colitis, IL-33 can increase the number of Foxp3+Tregs
The Tregs also play a immunosuppressive function in obesity-
associated inﬂammation (43). Interestingly, studies have also
demonstrated that IL-33 maintain homeostasis in adipose tissue.
A high level of ST2 expression is observed on human adipose
tissue Tregs. Furthermore, IL-33 treatment can induce vigorous
population expansion of Tregs in obese mice, and the changes
of metabolic parameters are signiﬁcantly correlated with the
increased Tregs (44,45). IL-33 signaling through the IL-33
receptor ST2 and the myeloid diﬀerentiation factor MyD88
pathway is essential for the development and maintenance
of Tregs in visceral adipose tissue (44). However, ILC2-
intrinsic IL-33 activation is required for Tregs accumulation
in vivo and is independent of ILC2 type 2 cytokines but
partially dependent on direct co-stimulatory interactions via
the inducible costimulator ligand (ICOSL)/ICOS pathway
Frontiers in Endocrinology | www.frontiersin.org 2January 2019 | Volume 10 | Article 26
Tu and Yang IL-33 Regulates Metabolic Disorders
FIGURE 1 | The regulatory role of IL-33 in metabolic diseases. IL-33/ST2 axis regulates metabolic diseases through: (1) promoting AAM polarization; (2) regulating the
differentiation and functions of Treg and Th2; and (3) regulating the function of ILC2.
(46). Concordantly, the ST2+Tregs population is with a
higher expression of activated marker ICOS and CD44
(38). Thus, IL-33 plays a protective role in adipose tissue
inﬂammation through directly and indirectly regulating Tregs
It has also been reported that increasing severity of insulin
resistance and microalbuminuria is strongly correlated with the
decreased level of IL-33 in patients with diabetic nephropathy,
where an enhanced Th1 and suppressed Th2 response is observed
(47). ST2 is selectively and stably expressed on the surface of
Th2 cells, and IL-33 can eﬀectively induce the immune response
of Th2 cells and the expression of Th2 related cytokines IL-5
and IL-13 without increasing IFN-γexpression (48,49). These
studies suggest that the ST2/IL-33 axis is closely associated
with the Th1/Th2 response imbalance in the development of
diabetes. Atherosclerosis is characterized by the formation of
ﬁbrotic plaques in the major arteries and increased Th1 immune
response, which leads to myocardinfal iarction and stroke (50,
51). It has been shown that Th1-to-Th2 shift can reduce the
development of atherosclerosis (52,53). Due to the eﬀect of IL-
33 on Th2-type immune response, IL-33 exhibits a protective
role in the pathogenesis of atherosclerosis (54). Previous ﬁndings
also showed that the reduced level of IL-33 might increase the
risk of atherosclerosis development for certain individuals (55).
These data suggest a crucial role of IL-33 in the lipid metabolism
through regulating T cells diﬀerentiation.
Due to the vital role of IL-33 in the metabolic homeostasis, a
sound understanding of the production, regulation, and function
of IL-33 will facilitate the treatment of metabolic disorders.
The potential mechanisms (Figure 1) of IL-33/ST2 axis in the
metabolic disorders may include: (1) IL-33 promotes the AAM
polarization; (2) IL-33 regulates Tregs and Th2 diﬀerentiation
and function; and (3) IL-33 regulates the function of ILC2.
Notably, the AAM polarization induced by IL-33 depends on
Type 2 cytokines, which may be released from ILC2. However,
most studies in this area were mainly carried out on animal
models and there were limited clinical trials. To what extent IL-
33 contributes to metabolic disorders in humans still requires
LT and LY reviewed the literature and wrote the ﬁrst draft. LY
ﬁnalized the manuscript. LT and LY have read and approved the
This work was supported by the National Natural Science
Foundation of China 81700490 to LT.
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Conﬂict of Interest Statement: The authors declare that the research was
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Copyright © 2019 Tu and Yang. This is an open-access article distributed under the
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