Journal of Inflammation Research Dovepress

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REVIEW

Role of Goblet Cells in Intestinal Barrier and

Mucosal Immunity
Journal of Inflammation Research downloaded from https://www.dovepress.com/ on 01-Apr-2022

Songwei Yang 1 Abstract: Goblet cells and the mucus they secrete serve as an important barrier, preventing
Min Yu 2 pathogens from invading the mucosa to cause intestinal inflammation. The perspective
1
regarding goblet cells and mucus has changed, with current evidence suggesting that they
Key Laboratory for Biorheological
Science and Technology of Ministry of are not passive but play a positive role in maintaining intestinal tract immunity and mucosal
Education (Chongqing University), homeostasis. Goblet cells could obtain luminal antigens, presenting them to the underlying
Chongqing University Cancer Hospital,
antigen-presenting cells (APCs) that induces adaptive immune responses. Various immuno­
Chongqing, 400030, People’s Republic of
For personal use only.

China; 2Department of General Surgery, modulatory factors can promote the differentiation and maturation of goblet cells, and the
Xinqiao Hospital, Third Military Medical secretion of mucin. The abnormal proliferation and differentiation of goblet cells, as well as
University, Chongqing, 400037, People’s
Republic of China
the deficiency synthesis and secretion of mucins, result in intestinal mucosal barrier dysfunc­
tion. This review provides an extensive outline of the signaling pathways that regulate goblet
cell proliferation and differentiation and control mucins synthesis and secretion to elucidate
how altering these pathways affects goblet functionality. Furthermore, the interaction
between mucins and goblet cells in intestinal mucosal immunology is described.
Therefore, the contribution of goblet cells and mucus in promoting gut defense and home­
ostasis is illustrated, while clarifying the regulatory mechanisms involved may allow the
development of new therapeutic strategies for intestinal disorders.
Keywords: goblet cell, intestinal tract, intestinal barrier, mucosal immunity, cytokine,
Mucin2

Introduction
The intestinal tract is essential in controlling nutrient digestion and absorption while
functioning as a barrier to prevent foreign antigens and pathogens from entering the
mucosal tissues and maintaining intestinal homeostasis. The intestinal barrier sys­
tem depends on interactions among several barrier components, including mucus
layer, epithelial layer and intercellular tight junctions and the lamina propria
underneath.1,2 Among these components, the integrity of the mucus barrier formed
by goblet cells and their secretions play a vital role in maintaining intestinal
homeostasis. Goblet cells secrete mucins, which are high-molecular-weight glyco­
proteins, denoting the primary structural element of the mucus layer.3,4 The mucins
are highly hydrophilic and can bind water to form a gel-like structure, preventing
direct contact between enterocytes and the intraluminal content, especially patho­
genic microorganisms.4 The absence of or any defect in the mucus layer allows
a large number of bacteria to make contact with the epithelial cells, triggering an
Correspondence: Songwei Yang; Min Yu
Tel/Fax +8623-653-10296; excessive immune response in the host,5 leading to colitis in mice.6 Various
+8623-687-55705 intestinal infections resulting from parasites,7,8 viruses,9 and bacteria10 modify the
Email yangsongwei01@126.com;
yumimianbao@163.com production of mucin and goblet cells, demonstrating the importance of the mucus

Journal of Inflammation Research 2021:14 3171–3183 3171

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layer in separating the luminal contents from the epithe­ involves a variety of complex signaling pathways, such as
lium. However, the critical function of the mucus layer and Wnt/β-catenin, Notch, PI3-kinase/Akt, and bone morpho­
goblet cells in host defense has not received adequate genetic protein (BMP) signaling.21 The canonical Wnt
attention. Recent studies have started to focus on the pathway is tightly linked with cell proliferation, differen­
ability of goblet cells to actively sense and respond to tiation and stem cell maintenance.15,22 Wnt ligands bind to
infections while secreting additional products, such as the Frizzled–LRP5–LRP6 receptor complex, which inhi­
trefoil factor peptides (TFF), mucins, Fc-γ binding protein bits continuous destruction of β-catenin by the cytoplasmic
(Fcgbp), and resistin-like molecule β (RELMβ), which are adenomatous polyposis coli (APC) destruction complex in
crucial in promoting intestinal defense.11–13 This review the intestinal epithelium.23 The accumulation of β-catenin
summarizes the current advancements regarding the sig­ leads to its translocation to the nucleus, where it binds
naling pathways that control goblet cell differentiation T cell factors (TCFs) and directly regulates gene
while discussing the new functional responsibility of gob­ expression.23 Using transgenic mice ectopically expressing
let cells in intestinal mucosal immunology. Dickkopf1 (Dkk1), a secreted Wnt inhibitor, Pinto et al24
found that epithelial proliferation is highly reduced simul­
The Differentiation of Goblet Cells taneously with the loss of crypts. Although enterocyte
The self-renewal of intestinal epithelial cells is maintained differentiation appeared unaffected, secretory cell lineages
by the proliferative activity of adult stem cells located at were largely absent. In the presence of WNT, stabilized β-
the base of the intestinal crypts. The progeny of these stem catenin can bind the Hes1 promoter together with Notch
cells proliferates and then differentiates into functional intracellular domain (NICD), resulting in stable Notch
epithelial subtypes that migrate to the villi and eventually activation and promoting the initial absorptive or secretory
into the lumen shed into the gut lumen.14,15 The four main cell differentiation decision by lateral inhibition.25,26
types, namely Paneth cells, intestinal epithelial cells, enter­ Higher up in the crypt, in the absence of WNT, negative
oendocrine cells, and goblet cells, are derived from the feedback of the Hes1 promoter and absence of nuclear β-
stem cells in the basement of the crypt.11 Enterocytes catenin causes oscillatory Notch activation and enables
represent the majority (up to 80%) of cells in the intestinal stochastic secondary fate decisions within a lineage (for
epithelium, they are responsible for ion, water, sugar, pep­ example goblet versus enteroendocrine cell fate26). The
tide and lipid uptake.15 The basal part of endocrine cells Notch signaling pathway significantly regulates intestinal
contains a large number of dense neuroendocrine granules, enterocyte lineage, activating the hairy and enhancer of
which contain the secreted peptide hormones, secreted split 1 (Hes1) transcription factor, repressing the basic
basally in an endocrine or paracrine manner.16 The goblet helix-loop-helix (bHLH) transcription factor mouse atonal
cell contains mucigen granules that are expelled to the homolog 1 (Math1),11,27 also known as Atonal homologue
surface as intestinal mucus, protecting and lubricating the 1 (Atoh1). The Notch-Hes1 pathway promotes intestinal
mucosa. Paneth cells are primarily located in the small progenitor cell differentiation toward luminal epithelial
intestine, where they secrete a number of mediators of cells, restricting the development of secretory cells.
host defense, including lysozyme, tumor necrosis factor, Notch signaling pathway activation disrupts the differen­
and defensins, that protect against intestinal bacterial tiation of secretory cells with the villi coated primarily with
pathogens.17 Dynamic analysis of the goblet cells in the absorptive enterocytes associated with Hes1 activation.11,21
intestines of mice indicated a migration from the crypt base Math1 facilitates the distinction of intestinal stem cells into
to the villi tip once after differentiation, where they enter the goblet cell lineage and is seemingly essential for differ­
the lumen.18,19 The upper crypt cells of the colon show that entiating intestinal secretory lineages since studies have
during differentiation, the goblet cells develop the capacity shown that Math1-deficient mice failed to generate three
to generate and store significant quantities of mucus.5 gastrointestinal mucosal cell types, namely enteroendo­
These immature goblet cells are located at the base of the crine, Paneth, and goblet cells.18,28 As indicated by pre­
crypt in a pyramidal shape.18 The goblet cell cannot be vious research, the transcriptional activation of the Jagged1
distinguished morphologically in Mucin2 (Muc2) deficient Notch-ligand, mediated by β-catenin, leads to Notch being
mice, despite the continued presence of other goblet cell downstream of Wnt in colorectal cancer cells.29,30
products, such as TFF.20 Maintaining stem cells and the Furthermore, the terminal differentiation of goblet cells
distinction into four main types of intestinal cell lineages involves the activation of Krüppel-like transcription factor

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4 (Klf4), SAM pointed domain-containing ETS transcrip­ 10 (IL-10), reversing an effect of aging in geriatric mice.41
tion factor (Spdef), and growth factor independence 1 Therefore, these results support the vital role of microbial
(Gfi1). As a downstream target of Math1, Gfi1 controls colonization in goblet cell development and maturation.
intestinal secretory cell subtype allocation and
differentiation.31 Furthermore, fewer supernumerary enter­
The Classification and Structure of
oendocrine and goblet cells were evident in Gfi1 knockout
mice, while they lacked Paneth cells. Gfi1-null crypts con­
Mucins
Mucins consist of large glycoproteins containing tan­
taining no Paneth cells and only a few goblet cells display
dem repeats with high levels of serine and threonine,
a quantitative reduction in Spdef, which is absent from
with the hydroxyl residues displaying a significant
Atoh1-null crypts lacking intestinal secretory cells, sug­
gesting Spdef functionality downstream of Gfi1 and number of O-linked oligosaccharides.4 To date, 21 dif­
Math1 in the goblet cell terminal differentiation ferent mucin genes have been detected, designated
pathway32 (Figure 1). In the intestine, Klf4 regulates goblet MUC1 to MUC21 according to the order of their
cell terminal differentiation by controlling Muc2 discovery.42 Furthermore, based on their structural
expression,33 which can be inhibited by the Notch signal­ characteristics and biological functionality, mucins are
ing pathway.34 Recent studies indicate that prolyl hydro­ segregated into two primary groups, namely mem­
xylase 3 (PHD3) also controls the generation of intestine brane-associated mucins and secreted mucins.
goblet cell by bounding the E3 ubiquitin ligase HUWE1 Intestinal membrane-associated mucins are denoted by
and inhibition of HUWE1-mediated ubiquitination and MUC1, MUC3A/B, MUC4, MUC12, MUC13, MUC15,
degradation of ATOH1.35 MUC17, MUC20, and MUC21. Secreted mucins can be
Various additional factors, such as immune cells, diet, divided into gel-forming mucins (MUC2, MUC5AC,
and bacteria, also influence goblet cell differentiation.36–38 MUC5B, MUC6, and MUC19), which are essential
Significantly fewer intestinal goblet cells in germ-free during the development of the mucus barrier on muco­
mice only express modest levels of MUC2 while contain­ sal surfaces, and non-gel forming mucins (MUC7,
ing an exceedingly thin mucus layer compared with con­ MUC8, and MUC9).42–46 Gel-forming mucins play
ventionally housed mice.39 However, exposing germ-free a functional protective, transportation, lubrication, and
mice to a conventional environment enhances RELMβ and hydration role in the mucous membranes.47 Minimal
MUC2 expression, leading to a substantially thicker mucus information is available regarding the functionality of
layer.40 The microbiota, acting via secreted factors related non-gel forming mucins. Membrane mucins provide
to indole, promote goblet cell differentiation and regulate a safe epithelial cell barrier while playing an important
intestinal homeostasis via the xenobiotic aryl hydrocarbon role in signal transduction.43 A summary of the mucin
receptor to increase expression of the cytokine interleukin- classification is listed in Table 1.

Figure 1 Role of transcription factors in goblet cell differentiation.

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Table 1 The Classification of Mucins Muc2 by binding to both the −1131 /−1100 and −676 /
Subfamily MUC Gene −650 sites.56 Moreover, NF-κB is also associated with the
upregulation of Muc2 transcription,57 representing the final
Membrane bound MUC1, MUC3, MUC4, MUC10, MUC11,
effector molecule that regulates Muc2 expression in multiple
MUC12, MUC13, MUC14, MUC15,
MUC16, MUC17, MUC18, MUC20, MUC21 signaling pathways (Figure 2).
Many other factors impact the expression of Muc2 by
Secreted Gel- MUC2, MUC5AC, MUC5B, MUC6, MUC19
directly binding on different sites of the promoter,
forming
including short-chain fatty acids (SCFAs),58 galectin-
Non Gel- MUC7, MUC8, MUC9
3,59 homeobox domains (Cdx),60 the GATA family,61
forming
and HATH1.62 SCFAs are metabolites formed by gut
microbiota from dietary fiber, including acetate, propio­
nate, and butyrate.63 As part of the β-galactoside-binding
Regulation of Mucin Synthesis gene family, galectin-3 is implicated in tumor progres­
The endoplasmic reticulum (ER) represents the organelle
sion, cell migration, adhesion, and apoptosis.59,64 Both
where mucins are synthesized, and N-linked glycosylation
butyrate and galectin-3 stimulate Muc2 expression
occurs. The assembled mucins are transported to the Golgi
through the AP-1 transcription factor binding site in the
complex, where they are O-linked glycosylated to a size of
Muc2 promoter.58,65 AP-1 is a dimeric protein complex
2.5 million Daltons.48–50 They are then packaged as secre­
that consists of c-Jun and c-Fos proto-oncogenes, the
tory granules, accounting for about 75% of the cytoplasmic
expression of which can be facilitated by butyrate.58
volume.51 The granules mature to produce highly concen­ Two Cdx-2 binding sites are present in the Muc2 pro­
trated mucins that eventually merge with the plasma mem­ moter at −177/-171 and −191/-187, suggesting that Cdx-
brane and are secreted into the extracellular domain.52 The 2 is a transcriptional regulator for Muc2.60 GATA exists
mucin structure changes to form a gelatinous combination in the Muc2 gene 5′-flanking region and comprises six
with water, covering the surface of the epithelium.49 MUC2 transcription factors in the highly conserved zinc finger
denotes the prominent intestinal mucin secreted by healthy DNA-binding domain, which is responsible for upregu­
mice, the deficiency of which leads to spontaneous inflam­ lating Muc2 gene expression.61,66 HATH1 and MATH1
mation and infection susceptibility.6 are bHLH transcription factors essential in regulating the
Recent studies have revealed that epigenetic and tran­ differentiation of goblet cells.18,28 HATH1 binding sites
scriptional regulation primarily controls the expression of are present in the Muc2 promoter sequence, the mutation
mucin.43,47,53 Signaling pathways control Muc2 transcrip­ of which down-regulates the expression of Muc2.62
tional regulation, activating the transcription factors binding Some bacterial products regulate the production of
to specific Muc2 promoter sites. Negative or positive Muc2 Muc2 indirectly by activating the NF-kB pathway, includ­
transcription is reportedly regulated by several biologically ing lipopolysaccharides (LPS), Gram-negative bacterial
active molecules, including growth factors, hormones, flagellin A, and Gram-positive bacterial lipoteichoic acid
microbial products, and cytokines.43 Muc2 gene expression (LTA). Muc2 transcription is upregulated by Gram-
regulation is essentially governed by the promoter region. negative Pseudomonas aeruginosa LPS by activating
The promoter structures of Muc2 reveal that a typical TATA NF-κB via the Ras-mitogen-activated protein kinase
box exists at the 31/−25 bp upstream location of the tran­ (MAPK) pathway in the intestinal epithelial cells.57,67
scriptional initiation site.54,55 The Muc2 gene 5′-flanking However, flagellin binds to the Asialo-GM1 glycolipid
areas display a CACCC box that specifically binds to the receptor on the surface, releasing ATP and subsequently
specificity protein 1 (Sp1) transcription factor. In addition, binding to the cell surface G protein-coupled receptor
transcription factor p53 can activate the transcription of (GPCR). This increases the intracellular calcium levels,

Figure 2 Schematic representation of the promoter regions of MUC2.

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activating NF-κB via the downstream signaling thickness of the mucus gel. It is constantly subjected to
pathways.57 Furthermore, LTA binds and activates the various microbial pathogens and stimuli and is often shed
platelet-activating factor receptor, a cell surface GPCR, due to peristaltic intestinal movements.75 The release of
inactivating the epidermal growth factor receptor mucin is accelerated when goblet cells are subjected to
(EGFR), in turn leading to the activation of the Ras/Raf/ powerful secretagogues and is influenced by many different
MEK/ERK/pp90rsk/NF-kB pathway while upregulating factors, including neuropeptides, cytokines, and lipids.76
the transcription68 of Muc2. Bioactive cytokine binds to specific receptor-affecting sec­
Furthermore, several cytokines and chemokines are ondary messengers and signaling components, such as intra­
involved in mucin synthesis. The Th1 type cytokine, cellular diacylglycerol, cAMP, and Ca2+, activating protein
tumor necrosis factor-α (TNF-α), upregulates the transcrip­ kinase C to promote the secretion67,77 of mucin. The pros­
tion of Muc2 via the PI3K/AKT/NF-κB signaling pathway. taglandin E2 (PGE2) immune modulator binds the EP4
Moreover, TNF-α also inhibits the transcription of Muc2 receptor, promoting cAMP-dependent exocytosis in the
through the JNK pathway, but overall effect of is a net human colon.78,79 Carbachol, a Ca2+-mediated agonist, ele­
increase in Muc2 transcription, because NF-κB transcrip­ vates the cytosol levels of Ca2+, which stimulates the
tional activation of this gene is able to counter-balance the secretion80 of mucin. Phorbol 12-myristate 13-acetate
suppressive effects of the JNK pathway.69 However, TNF-
(PMA) significantly promotes the release of mucin via the
α inhibited Muc2 production when NF-κB was inactivated,
protein-kinase C-dependent pathway.77
which gives rise to the defective mucosal protection.69
Recent research has indicated that the mucus secretion
Vasoactive intestinal peptide (VIP), a neuropeptide hor­
of goblet cells is modulated by several cellular processes,
mone, is responsible for the Muc2 transcription upregula­
including the assembly and activation of inflammasomes,
tion by activating the CREB/ATF1 transcription factors via
the generation of reactive oxygen species (ROS),4,5,81
the p38 and MAPK pathways.70 PGE2 also induced Muc2
autophagy, and endocytosis. Previous research has
transcription by activation of CREB/ATF1. The underlying
revealed the inhibition of clathrin-mediated endocytosis,
molecular mechanisms of another Th1 type cytokine, IL-
as well as defects in autophagy-related proteins, including
1β, induces the Muc2 activation of the p38 and ERK
Atg5, Atg14, and FIP200, resulting in the aggregation of
pathways, leading to cyclooxygenase 2 expression, an
goblet cell mucin granules.4,81 Mucin accumulation is not
enzyme related to PGE2 synthesis.71 Moreover, IL-4 and
associated with mucin expression, suggesting that this
IL-13 are Th2 cytokines that can upregulate the expression
effect might be caused by mucin secretion deficiency.
of Muc2 through the MAPK/NF-κB mediated pathway.72
Recent studies have shown that the secretion of goblet
Epigenetic regulation includes microRNA silencing,
cells relies on autophagy proteins.81 The MUC2 granule
histone modification, and DNA methylation. The methyla­
tion of specific CpG sites in the promoter region and first aggregation in the goblet cells is determined via a targeted
intron of Muc2 is associated with the repression of villin-driven deficiency of the Atg5 autophagy protein in
MUC2.73 Recent studies have revealed that the expression the intestines of mice. This process is mediated by ROS
of Muc2 gene is controlled by the methylation of DNA derived from NADPH oxidases.
and the modification of histone in the 5′ flanking area of The NLR protein, NLRP6, is associated with inflamma­
the Muc2 promoter.74 some signaling and is essential for maintaining intestinal
homeostasis.82,83 In NLRP6 knock out mice, goblet cells
Regulation of Mucin Secretion were less efficient at secreting mucin and had poorer devel­
After mucin proteins are synthesized in the goblet cells, they opment of the inner mucus layer.83 No reduction was evident
are tightly packed into intracytoplasmic granules. They are in the specific protein transcription of goblet cells in NLRP6-
then transported to the surface of the cell and ultimately deficient mice, suggesting that the lack of mucus generation
secreted into the lumen. Mucin secretion can be divided into could not be attributed to a decline in transcript production.
two types, namely constitutive and stimulated secretion. In Conversely, the accumulation of intracellular mucin particles
typical physiological conditions, goblet cells are synthesized in the distal colon of mice deficient in NLRP6 increased, but
continuously, secreting mucins to form the hydrated gel these particles failed to merge with the apical surfaces of the
coating on the intestinal mucosal luminal surface. This con­ goblet cells. NLRP6 deficiency resulted in defective goblet
tinual secretion of mucin is essential for maintaining the autophagy, reducing mucin secretion into the intestinal lumen.

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Recent reports indicated that some goblet cells localized mucus, recent studies have shown that this is not the case. The
at the colonic crypt entrance underwent nonspecific endocy­ intestinal lamina propria (LP) has a large population of den­
tosis, known as sentinel goblet cells (senGC). Toll-like recep­ dritic cells, such as CD103- CX3CR1+ antigen-presenting
tors (TLR)-ligands, LPS, and P3CSK4 were endocytosed by cells (APCs) with macrophage qualities and CD103+
senGC, triggering TLR-MyD88 signaling and inducing CX3CR1- APCs with dendritic cell characteristics.85–87 In
downstream ROS synthesis, causing NLRP6 inflammasome- CD103+ APCs, retinaldehyde dehydrogenase (ALDH1)
mediated caspase 1 and 11 activation. Furthermore, this led expression is essential for producing all-trans retinoic acid
to the Ca2+-dependent exocytosis of MUC2 and intercellular (ATRA), which plays various roles in the mucosal immune
signaling connections, prompting the secretion of MUC2 by response to lumen antigens, such as promoting IgA responses,
the adjacent responsive GCs. The inhibition of endocytosis or imprinting lymphocytes with gut homing, and prompting reg­
NADPH/Dual oxidase ROS synthesis restricted TLR-ligand- ulatory T cell formation.86,88,89 The CD103- CX3CR1+ APCs
induced Muc2 secretion12,84 (Figure 3). are crucial for the formation of Th17 T cells, colitis, and the
production of TNF-α.90 Research has revealed that intestinal
The Interaction Between Goblet epithelial cells can also obtain luminal antigens, presenting
Cells and Immune Cells them to the dendritic CD103+ cells underlying the LP in
Although the main functions of intestinal goblet cells have a way that induced adaptive immune responses, known as
traditionally been believed to include producing and secreting goblet-cell-associated antigen passages (GAP cells86,91).

Figure 3 Regulatory mechanism of mucus secretion in goblet cell and interaction with immune cells. Soluble antigens in the lumen of the intestine such as LPS and P3CSK4
are endocytosed by senGC, triggering TLR-MyD88 signaling, ROS synthesis and NLRP6 inflammasome, causing Ca2+-dependent secretion of MUC2. Goblet cells can also
deliver luminal antigens to APCs, initiating adaptive responses.

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When acetylcholine (ACh) acts on muscarinic acetylcholine IL-13 are considered the major effector cytokines that signal
receptor 4 (mAChR4) on the goblet cells, GAPs are formed.92 through the IL-4Rα and IL13Rα1 subunits on the intestinal
The formation of GAPs occurs in a steady state in the small epithelial cells to induce goblet cell hyperplasia via the down­
intestine, but is inhibited by Myd88 dependent microbial sen­ stream signal transducer and activator of transcription factor 6
sing in the colon. According to Knoop KA, GAP cells could (STAT6) signaling.103,104 STAT6 is critical for goblet cell
occur in the colon following treatment with antibiotics, that hyperplasia development during infection with
18,105
they were repressed by TLR ligands in a goblet cell intrinsic T. spiralis. STAT6 deficient mice infected with
Myd88-dependent manner. The EGFR and MAPK are acti­ T. spiralis failed to generate infection-induced goblet cell
vated by Myd88, inhibiting the formation of colon GAPs. hyperplasia. Further studies have shown that IL-13 is crucial
Therefore, both CD103− and CD103+ dendritic cells, as well in regulating goblet cell hyperplasia in Gymnophalloides seoi
as subsequent mucosal inflammation, are activated92 infection. The overexpression of IL-13 in mice causes the
(Figure 3). development of goblet cell hyperplasia in their intestines.
Goblet cell products and luminal antigens are transferred Furthermore, the overexpression of exogenous IL-9 and IL-
during the interaction with APCs, imprinting them with muco­ 25 promotes goblet cell proliferation and mucin expression via
sal properties.86 The primary goblet cell product, MUC2, has an IL-13-reliant pathway.106 The administration of IL-4
been shown to imprint anti-inflammatory gene markers enhances the thickness and quality of the mucus while decreas­
required for oral tolerance on APCs.93 Interfering with the ing pathogenic contact with the epithelium in C. rodentium and
APC and epithelial cell interaction reduces the transfer of colitis in infected mice.107 IL-13 and IL-4 upregulate the
goblet cell products to APCs, reducing the induction of muco­ expression of specific goblet cell products, TFF3 and MUC2,
sal reactions.94 RELM-β is another product secreted by goblet via STAT6 signaling.108 In addition, IL-13 and IL-4 increase
cells, acting as a chemoattractant recruit CD4 T cells to the the transcription of MUC2 through the MAPK pathway72
colon LP when infected with C. rodentium95 CD4+ T cell (Figure 4).
recruitment to the infected colons of RELM-β knockout mice Like Th2 cytokines, some Th1 cytokines regulate mucin
was restricted, reducing IL-22 production, a pluripotent cyto­ biosynthesis, while TNF-α upregulates MUC2 in human
kine directly responsible for enhancing the proliferation of intestinal epithelial cells via the NIK and PI3K/Akt signaling
epithelial cells. Goblet cells also regulate the immune response pathways converging at the common NF-κB pathway.69
by secreting various cytokines, such as IL25, IL18, IL17, IL15, MUC2 was increased in the 3D co-culture model of Caco-2
IL13, IL7, and IL6, and chemokine exotoxin, CCL6, CCL9, and HT29-MTX cells when treated with IL-1β, while
and CCL20. The latter attract APCs to the epithelium.91,94 MUC5AC remained unchanged.109 By activating PI3K and
Therefore, goblet cells establish intimate interactions with PKC-MEK/ERK, IL-1β also stimulates the secretion of mucin
immune cells, playing a unique and integral role in maintaining and the expression of MUC2 genes in the epithelial cells of the
gut immune homeostasis.96 human airway.110 In contrast, the Th1 cytokines, TNF-α and
IFN-γ, decrease the production of intestinal mucin, as well as
the mucin transportation rate from the Golgi to secretory
Immune Regulation of Goblet Cell vesicles in the C. rodentium infection mode,107 implying that
Function the Th1 cytokine impact on goblet cells is not only related to
Although goblet cells control the LP via a specific mechanism, the type of cytokines but also pathological conditions.
the immune system is also essential in regulating goblet cell Studies have shown that the Th17-associated cytokine,
functionality (Figure 4). Type 3 Innate Lymphoid Cells IL-22, is essential in regulating the expression of mucin
(ILC3s) promotes goblet cell differentiation and the expression and the differentiation of GC. IL-22 knockout mice fail to
of MUC2 through the lymphotoxin (LT)-LTβR pathway dur­ increase the expression of MUC2 and reduced goblet cell
ing intestinal listeria infection.10,97 DCs such as macrophages hyperplasia in N.brasiliensis and T. muris infection.111
and dendritic cells provide processed, phagocytosed antigens This is correlated with the reduced induction of TH2
for activating and instructing naïve CD4+ T cells to convert to immunity as IL-4, IL-5, and IL-13 declined.112 In
type 2 helper (Th2) cells.98,99 These cells are essential for the a mouse colitis model, IL-22 was directly responsible for
immune response against extracellular parasites and intracel­ mucin gene expression in the mucosal epithelial cells via
lular pathogens, resulting in the increased secretion of cyto­ goblet cell restitution and STAT3-reliant signaling, alle­
kines like IL-13, IL-9, IL-5, and IL-4.100–102 Of these, IL-4 and viating local intestinal inflammation.113,114

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Figure 4 Immune regulation of goblet cell function and mucin production. (1) IL-33 and IL-25 activate ILC2 and Th2 cells during parasite infections, which release Th2
cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 can promote goblet cell proliferation through STAT6 signaling. IL-4 and IL-13 also upregulate the expression of
TFF3 and MUC2 via STAT6 or MAPK signaling. IL-25 and IL-9 also promoted goblet cell proliferation and mucin expression through IL-13 dependent pathway. IL-33 induces
goblet cell differentiation by stimulating ILCs to produce IL-13. (2) Th1 cytokines such as TNF-α, IL-1β and IFN-γ play complex way in regulating mucin biosynthesis, which
not only induce, but also inhibit MUC2 expression in different pathophysiological conditions. (3) IL-22 can regulate goblet cell differentiation and induces mucin expression in
STAT3 signaling. IL-10 promotes mucin expression by inhibiting protein misfolding and ER stress in goblet cells.

As an anti-inflammatory cytokine, IL-10 inhibits Conclusions

macrophage activation and inflammatory response.115,116 Mucin is the primary secretory product of goblet cells and is
The expression of IL-10 in normal subjects was higher responsible for generating mucus layers, protecting against
than in inflammatory bowel disease (IBD) patients.117 IL- pathogen invasion in the intestinal mucosa. These mucus
10 knockout mice were used for the animal inflammation layers are essential in preventing pathogenic microbial inva­
model.118 The goblet cell count decreased in IL-10 defi­ sion and colonization while establishing commensal intest­
cient mice compared with wild-type mice.119 Recent stu­ inal microbiota. In recent years, several studies have
dies have also shown that IL-10 has a direct impact on examined the molecular mechanisms of mucin biology and
goblet cell mucus production and mucosal the regulatory pathways responsible for the secretion and
120
characteristics. Moreover, previous studies suggest that biosynthesis of mucin. This data can help develop new
IL-10 restricts ER stress and protein misfolding in goblet strategies to treat the abnormal mucin expression that is
cells, enhancing intestinal mucus production.121 often present in inflammatory and malignant diseases.
The IL-1 cytokine, IL-33, increases in response to infec­ Furthermore, while the primary function of goblet cells is
tion and colitis122 while prompting the production of the IL-4, to maintain the integrity of the intestinal barrier, the compli­
IL-5, and IL-13 Th2 cytokines from innate lymphoid cells cated contribution of these cells to mucosal immunity far
(ILCs) and T cells.123 IL-33 prevented goblet cell depletion by exceeds the mere secretion of mucus. Notably, goblet cells
inhibiting Notch1 signaling in a dextran sulfate sodium (DSS)- are now considered active participants in defending the host,
induced mouse colitis model.124 Research has shown that IL- reacting to their luminal environment in conjunction with
33 prompts the production of IL-13 by stimulating ILCs, the immune response. This review summarizes the crucial
indirectly inducing epithelial goblet cell differentiation.37 nature of the immune system in regulating the biological

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functions of goblet cells. In conclusion, further research is 7. Khan WI. Physiological changes in the gastrointestinal tract and
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goblet cell differentiation via the LT-LTbetaR pathway during
APCs, antigen-presenting cells; TFF, trefoil factor peptides;
listeria infection. J Immunol. 2020;205(3):853–863. doi:10.4049/
Fcgbp, Fc-γ binding protein; RELMβ, resistin-like molecule jimmunol.2000197
β; BMP, bone morphogenetic protein; Hes1, hairy and 11. Kim YS, Ho SB. Intestinal goblet cells and mucins in health and
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enhancer of split 1; Muc2, Mucin2; Math1, mouse atonal 2010;12(5):319–330. doi:10.1007/s11894-010-0131-2
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A sentinel goblet cell guards the colonic crypt by triggering
prolyl hydroxylase 3; ER, endoplasmic reticulum; SCFAs,
Nlrp6-dependent Muc2 secretion. Science. 2016;352
short-chain fatty acids; LPS, lipopolysaccharides; LTA, lipo­ (6293):1535–1542. doi:10.1126/science.aaf7419
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This work was supported by the Basic Science and Frontier 0048-1
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epithelium of the mouse small intestine. Am J Anat. 1969;124
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