Inflammation, Vol. 39, No.

6, December 2016 ( # 2016)

DOI: 10.1007/s10753-016-0442-z

ORIGINAL ARTICLE

Role of NLRP3 Inflammasome in Eosinophilic

and Non-eosinophilic Chronic Rhinosinusitis with Nasal Polyps

Hai Lin,1,2,5 Zhipeng Li,1 Dong Lin,3 Chunquan Zheng,4 and Weitian Zhang1,5

Abstract—The pathophysiologic mechanisms of human chronic rhinosinusitis with nasal polyps (CRSwNP)
remain unclear. We aimed to elucidate expression and biologic role of NLRP3 inflammasome in CRSwNP.
Immunohistochemistry (IHC) was conducted to assess NLRP3 immunolabeling, real-time polymerase chain
reaction (PCR) was used for IL-9 and NLRP3, and caspase-1 level quantitation in CRSwNP and control
subjects. In addition, enzyme-linked immunosorbent assay (ELISA) was employed for analyzing concen-
trations of IL-1β and IL-18 in the homogenates prepared from tissue specimens. Moreover, human nasal
epithelial cells (HNECs) were used to evaluate the effects of lipopolysaccharide (LPS) and glyburide on
NLRP3 inflammasome signaling pathway. Results showed that NLRP3 and caspase-1 were overexpressed in
CRSwNP, especially in eosinophilic CRSwNP (ECRSwNP). Interestingly, NLRP3 expression had close
correlation to that of caspase-1. Concentrations of IL-1β and IL-18 were elevated. NLRP3 inflammasome
signaling pathway was augmented by LPS but suppressed by glyburide. In conclusion, NLRP3 inflamma-
some signaling pathway played a pro-inflammatory role in the pathogenesis of CRSwNP, especially in
ECRSwNP. NLRP3 inflammasome signaling pathway was augmented by LPS, but suppressed by glyburide.

KEY WORDS: NLRP3; caspase-1; eosinophil; glyburide; chronic rhinosinusitis; nasal polyps.

INTRODUCTION inflammation plays a critical role in the pathogenesis of

Chronic rhinosinusitis with nasal polyps (CRSwNP)
is a common nasal inflammatory disease, characterized by
nasal blockage, nasal discharge, a lost sense of smell, and
headache [1, 2]. There is ample evidence that eosinophilic
Hai Lin, Zhipeng Li and Dong Lin contributed equally to this work.
1
Department of Otorhinolaryngology, Shanghai Jiao Tong University
Affiliated Sixth People’s Hospital, Shanghai, 200233, China
2
Department of Otorhinolaryngology, Fuzhou General Hospital, Fuz-
hou, 350025, Fujian, China
3
Department of Biology and Chemical Engineering, Fuqing Branch of
Fujian Normal University, Fuqing, 350300, Fujian, China
4
Department of Otorhinolaryngology, Eye and ENT Hospital of Fudan
University, Shanghai, 200031, China
5
To whom correspondence should be addressed at Department of
Otorhinolaryngology, Shanghai Jiao Tong University Affiliated Sixth
P e o p l e ’s H o s p i t a l , S h a n g h a i , 2 0 0 2 3 3 , C h i n a . E - m a i l s :
lhi2012@sina.com; drzhangwt@sina.com
CRSwNP in white subjects [3, 4]. Nevertheless, recent
work has revealed that over half of the Chinese CRSwNP
patients showed non-eosinophilic inflammation histologi-
cally [5].Therefore, it is necessary to classify CRSwNP
based on eosinophils number to investigate the pathogen-
esis of CRSwNP.
There is ample evidence that NOD-like receptors
(NLRs) are key pattern recognition receptors in combating
pathogens and play critical roles in the activation and
regulation of innate immune response [6, 7]. NLRP3, also
known as cryopyrin, a member of the NLR family, can be
activated by pathogens, sterile tissue damage, or metabolic
stress and plays a pivotal role in the process of inflamma-
tory reactions [8, 9]. There is mounting evidence indicating
that NLRP3 is a key component of a multiprotein complex
(NLRP3 inflammasome) serving as a pattern recognition
receptor and a trigger of the activation of caspase-1 and the
maturation of IL-1β and IL-18 [10, 11]. Recent work has

2045
0360-3997/16/0600-2045/0 # 2016 Springer Science+Business Media New York
2046
revealed that NLRP3 plays a pivotal role in the chronic
airway inflammatory diseases like asthma and chronic
obstructive pulmonary disease (COPD) by triggering in-
flammatory cells recruitment and pro-inflammatory cyto-
kines release [12–16]. However, its role in the pathogenesis
of CRSwNP remains uncertain. Therefore, we aimed to
elucidate expression and biologic role of NLRP3 inflam-
masome in CRSwNP.
MATERIALS AND METHODS
Subjects
A total of 67 CRSwNP and 25 control subjects were
included in this study. Immunohistochemistry (IHC), real-
time polymerase chain reaction (PCR), enzyme-linked im-
munosorbent assay (ELISA), and human nasal epithelial
cells (HNECs) experiments were used. Diagnostic criteria
of CRSwNP were refered to the related literature [17].
Histologically, more or equal to 10 % for the ratio of
eosinophils to total inflammatory cells was diagnosed as
eosinophilic CRSwNP (ECRSwNP) and less than that was
diagnosed as non-eosinophilic CRSwNP (nECRSwNP) as
described previously [5]. We collected human normal nasal
mucosas of the inferior turbinate from 25 patients under-
going septorhinoplasty. Subject informations are listed in
Table 1. Additionally, subjects taking any immunosuppres-
sant, anti-histamine, antibiotic, or steroid 1 month before
the surgery were excluded.
Surgical samples were divided into several sections
for hematoxylin–eosin (HE), IHC, real-time PCR, ELISA,
or HNEC culture. NLRP3 protein levels were analyzed
using IHC, messenger RNA (mRNA) expression of
NLRP3 and caspase-1 was assessed using real-time PCR,
and homogenates prepared from tissue specimens were
Table 1. Characteristics of Included Subjects
Characteristics ECRSwNP
No. of subjects 32
Age, year, median (IQR) 35.5 (25.5–47.0)
Sex, male, no. (%) 17/15 (53.1)
Total VAS scores, median (IQR) 15.8 (9.5–20.0)
Endoscopy score, median (IQR) 9.2 (4.5–11.5)
CT scores, median (IQR) 17.2 (12.0–21.0)
Patients with smoking, no. (%) 15 (46.9)
Patients with asthma, no. (%) 3 (9.4)
Patients with atopy, no. (%) 17 (53.1)
ECRSwNP eosinophilic chronic rhinosinusitis with nasal polyps, nECRSwNP non-eosinophilic chronic rhinosinusitis with nasal polyps, VAS visual analog
scale, N/A not applicable, CT computed tomography
Lin, Li, Lin, Zheng, and Zhang
analyzed for concentrations of IL-1β and IL-18 by ELISA.
Additionally, the effects of lipopolysaccharide (LPS) and
glyburide on NLRP3 inflammasome signaling pathway
were evaluated on HNECs culture. This study was ap-
proved by the ethical committees of Shanghai Jiao Tong
University Affiliated Sixth People’s Hospital and Fuzhou
General Hospital, and an informed consent was provided
from every subject.
Eosinophils Counting and Immunohistochemistry
HE and IHC staining of paraffin tissue sections was
performed as previously reported [18, 19]. Briefly,
paraformaldehyde-fixed and paraffin-embedded tissues
were cut serially at 5 μm. We counted eosinophils number
at high power (HP) magnification (×400) and selected 10
HP fields randomly and microscopically. Histologically,
more or equal to 10 % for the ratio of eosinophils to total
inflammatory cells was diagnosed as eosinophilic
CRSwNP and less than that was diagnosed as non-
eosinophilic CRSwNP as described previously [5]. IHC
staining procedure was performed using the streptavidin
biotin complex (SABC) kit (Boster Biological Technolo-
gy). Briefly, after deparaffinization and rehydration, the
tissue sections were microwaved for 10 min in citrate
buffer for antigen retrieval and then incubated with primary
rabbit polyclonal antibody against NLRP3 (1:100, Wuhan
Boster Biological Technology) overnight at 4 °C to stain
target protein expression. Following 20-min incubation of
secondary anti-rabbit antibody, 3,3-diaminobenzidine
(DAB) was applied for visualizing immunoreactivity. Pos-
itively stained cells in 10 different areas were counted
microscopically. The integrated optical density (IOD) of
NLRP3 immunoreactivity was analyzed by Image pro plus
6.0 (Media Cybernetics) as described previously [20].
nECRSwNP Controls P value (ECRSwNP vs. nECRSwNP)
35 25 N/A
36.5 (27.3–49.0) 33.0 (25.0–50.0) 0.799
18/17 (51.4) 13/12 (52.0) 0.890
13.0 (7.0–18.5) N/A 0.010
7.2 (3.0–10.0) N/A 0.008
15.0 (11.0–19.0) N/A 0.015
16 (45.7) 11 (44.0) 0.924
0 (0) 0 (0) 0.104
8 (22.9) 0(0) 0.011
Role of NLRP3 Inflammasome in Eosinophilic and Non-eosinophilic Chronic Rhinosinusitis with Nasal Polyps
RNA Extraction, Reverse Transcription,
and Real-Time PCR
Each surgical specimen was snap frozen in liquid
nitrogen within 15 min of collection and stored at
−80 °C. Total RNA was extracted using the TRIzol reagent.
Absorbance ratios at 260/280 nm (1.8∼2.0) were used to
assess the purity of RNA. We used Superscript First-Strand
Synthesis System (Invitrogen) for reverse transcription.
Two-microgram total RNA was transcribed reversely into
cDNA as a template for real-time PCR.
We used Platinum SYBR Green qPCR SuperMix
(Invitrogen) to detect the mRNA expression of NLRP3 and
caspase-1. Primers were designed and synthesized (Sangon
Biotech, Shanghai, China). NLRP3 (110 bp) primers were as
follows: forward primer, 5-AAGGAAGTGGACTG
CGAGAA-3 and reverse primer, 5-ACGTTCGTCCTTCC
TTCCTT-3. Caspase-1 (147 bp) primers were as follows:
forward primer, 5-AACTGGAGCTGAGGTTGACA-3 and
reverse primer, 5-TCAGAGGTCTTGTGCTC TGG-3. The
internal control GAPDH (112 bp) primers were as follows:
forward primer, 5-TCGTGGAAGGACTCATGACC-3 and
reverse primer, 5-ATGATGTTCTGGAGAGCCCC-3. Rela-
tive mRNA level was expressed as the relative fold change
and calculated using the formula: 2−ΔΔCT = 2−(ΔCT(Sample)
− ΔCT(Calibrator)) where each ΔCT = ΔCTTarget − ΔCTGAPDH.
A designated calibrator was from one control sample without
any intervention.
ELISA Assay
After homogenization and centrifugation of freshly
obtained tissue specimens or HNECs, the expression levels
of IL-1β and IL-18 in the supernatants were determined
using ELISA kits (R&D systems) according to the manu-
facturer’s instructions.
HNECs Culture and Stimulation
Cell Culture and Stimulation
HNECs isolated from six CRSwNP patients were
cultured as described previously [21]. Briefly, following
PBS washing of nasal specimens, they were immersed in
DMEM/F12 (Sigma) containing 0.1 % protease type XIV
for overnight incubation at 4 °C and protease activity was
blocked by 10 % FBS (Sigma). Then, we filtered cell
suspensions and centrifuged at 1200 rpm for 5 min. We
washed the epithelial cells with PBS (37 °C, pH 7.4) and
cultured them into DMEM containing 20 % FBS. The
HNECs were incubated with either 20 μl PBS (blank
control), 10 μl LPS (1 μg/ml, a priming signal and NLRP3
2047
activator, Sigma-Aldrich) + 10 μl glyburide (200 mM, a
selective NLRP3 inhibitor, Sigma-Aldrich), or 20 μl LPS
(1 μg/ml) for 24 h. Following stimulation, the cells were
harvested for assaying NLRP3 and caspase-1 protein by
western blotting, and the supernatants were collected for
assaying IL-1β and IL-18 protein levels by ELISA.
Western Blotting
The expression of NLRP3 and caspase-1 was deter-
mined by western blot analysis. Briefly, total cellular pro-
tein was extracted and separated using RIPA Buffer
(Pierce) and transferred onto polyvinylidene difluoride
membranes. The membranes were then incubated with
the primary antibody (rabbit anti-human NLRP3, 1:200
dilution, Boster Biological Technology; rabbit anti-human
caspase-1, 1:200 dilution, Boster Biological Technology)
overnight at 4 °C, and then incubated with the goat anti-
rabbit IgG-HRP (Boster Biological Technology). Immuno-
reactions were detected by Enhanced Chemiluminescence
(ECL) Kit (Pierce). Gray value of targeted gene was nor-
malized to that of the housekeeping gene (β-actin).
Statistical Analysis
Statistical analysis was carried on SPSS software
(version 20.0). Continuous variables were expressed as
medians and interquartile ranges or in box and whisker
plots displaying medians and interquartile ranges and ana-
lyzed via non-parametric Mann–Whitney U test and Krus-
kal–Wallis H test. For in vitro experiment, data were
expressed as mean ± standard deviation and were analyzed
with one-way ANOVA test. The Spearman’s test was used
to determine correlations. Chi-squared test was used to test
differences in proportions between groups. A P value
<0.05 was accepted as significant.
RESULTS
Characteristics of Included Subjects
Overall, we included 25 control subjects and 67
CRSwNP patients involving 32 ECRSwNP and 35
nECRSwNP patients. Of the documented data in
Table 1, the three groups of subjects were not sig-
nificantly different with respect to age and gender
distribution (P > 0.05). Importantly, total VAS score,
endoscopy score, CT score, and patients with atopy
were significantly higher in ECRSwNP group than
that in nECRSwNP group (P < 0.05).
2048 Lin, Li, Lin, Zheng, and Zhang

Fig. 1. Immunolabeling of NLRP3 in control group (a), nECRSwNP group (b), and ECRSwNP group (c).NLRP3 protein levels were significantly over-
expressed in CRSwNP groups compared with control group and were significantly stronger expressed in ECRSwNP group compared with nECRSwNP
group (a–d). Kruskal–Wallis H test was employed for comparison.*P < 0.05.

Fig. 2. NLRP3, caspase-1, IL-1β, and IL-18 levels were elevated in CRSwNP groups compared with control group, and these were also found in ECRSwNP
group compared with nECRSwNP (a–d). Kruskal–Wallis H test was employed for comparison.*P < 0.05.
Role of NLRP3 Inflammasome in Eosinophilic and Non-eosinophilic Chronic Rhinosinusitis with Nasal Polyps 2049

NLRP3 Inflammasome Immunoreactivity in Nasal upregulated in CRSwNP groups, especially in ECRSwNP

Tissues
IHC staining showed that NLRP3 inflammasome was
expressed in nasal epithelial cells and submucosal inflam-
matory cells (Fig. 1a–c). Compared with control group,
NLRP3 inflammasome was significantly overexpressed in
CRSwNP groups, especially in ECRSwNP group
(P < 0.05; Fig. 1d).
NLRP3 and Caspase-1 mRNA Levels in Nasal Tissues
Compared with control group, mRNA levels of
NLRP3 and caspase-1 were found to be significant
group (P < 0.05; Fig. 2a, b). Additionally, there was a
significant correlation between NLRP3 mRNA level and
caspase-1 mRNA level in CRSwNP groups (Spearman’s
test, r = 0.783, P < 0.05).
IL-1β and IL-18 Protein Levels in Nasal Tissues
The results of ELISA indicated that IL-1β and IL-18
protein levels in nasal tissues from CRSwNP group were
found to be significantly higher compared with that from
control group (Fig. 2c, d). IL-1β and IL-18 protein levels
were higher in ECRSwNP group compared with

Fig. 3. Significantly increased NLRP3, caspase-1, IL-1β, and IL-18 levels in cultured HNECs was found after incubation with LPS and LPS + Gly (a–e).
Significant decrease of NLRP3, caspase-1, IL-1β, and IL-18 levels in cultured HNECs was found after incubation with LPS + Gly group compared with LPS
group (a–e). Values were shown as mean ± standard deviation. One-way ANOVA test was used for the statistical analysis.*P < 0.05.
2050
nECRSwNP group (P < 0.05). These findings were con-
sistent with the changes in the NLRP3 and caspase-1 levels
in nasal tissues.
NLRP3 and Caspase-1 Protein Levels in HNECs
To further illustrate the role and mechanism of NLRP3
inflammasome signaling pathway in CRSwNP, HNECs
were intervened with LPS acting as harmful pathogen and
glyburide serving as a specific inhibitor of NLRP3 inflam-
masome signaling pathway. As indicated in Fig. 3a–c, com-
pared with control group, stronger bands of NLRP3 and
caspase-1 protein were found in the LPS or LPS+ glyburide
group, respectively (P < 0.05), whereas weaker bands were
detected in LPS + glyburide group compared with LPS
group (P < 0.05). NLRP3 and caspase-1 levels were en-
hanced by LPS but suppressed by glyburide.
IL-1β and IL-18 Protein Levels in HNECs
As indicated in Fig. 3d, e, compared with LPS group,
higher levels of IL-1β and IL-18 protein were found in the
LPS or LPS + glyburide group compared with control
group (P < 0.05), respectively, whereas lower levels were
detected in LPS + glyburide group (P < 0.05). NLRP3 and
caspase-1 levels were enhanced by LPS but suppressed by
Fig. 4. Schematic diagram of the role of NLRP3 in the pathogenesis of CRSwNP.
Lin, Li, Lin, Zheng, and Zhang
glyburide. These findings were in line with the changes in
the NLRP3 and caspase-1 levels in HNECs.
DISCUSSION
In the present study, we compared NLRP3 inflamma-
some in different types of CRSwNP classified by the ratio
of eosinophils to total inflammatory cells histologically
and demonstrated that ECRSwNP presented more severe
form of inflammation than nECRSwNP, which was in line
with the published reports [22, 23].
Considerable data indicate that activation of NLRP3 is
triggered following being combined with caspase-1 and then
IL-1β and IL-18 are maturated, which play pivotal roles in
cell growth, proliferation, and survival [24–26]. In this study,
we demonstrated that NLRP3, caspase-1, IL-1β, and IL-18
levels were significantly higher in CRSwNP group, com-
pared with control group, especially in ECRSwNP group.
Additionally, there was a significant correlation between
NLRP3 mRNA level and caspase-1 mRNA level in
CRSwNP groups, indicating a synergistic action of NLRP3
and caspase-1 in the pathogenesis of CRSwNP. Meanwhile,
IL-1β and IL-18 protein levels in CRSwNP group were
significantly higher compared with control group, which
were consistent with the changes of the NLRP3 and
Role of NLRP3 Inflammasome in Eosinophilic and Non-eosinophilic Chronic Rhinosinusitis with Nasal Polyps
caspase-1 levels in nasal tissues.The results indicated that
NLRP3 played a pivotal role in promoting epithelial cell
growth and inflammatory cells infiltration in CRSwNP, and
the effect of NLRP3 is more obvious in ECRSwNP.
Considerable data indicate that due to the good repre-
sentative of HNECs for human nasal polyps and convenient
isolation of HNECs from human nasal polyps, they are most
often applied to deeply explore the regulation of targeted
gene in the pathophysiology of CRSwNP [27–29]. In the
present study, to explore the cellular and molecular mecha-
nisms of regulation of NLRP3, HNECs were incubated with
LPS acting as a priming signal and NLRP3 activator or LPS
plus a selective NLRP3 inhibitor glyburide. We found that
NLRP3 inflammasome signaling pathway was significantly
induced by LPS but suppressed by glyburide, indicating that
LPS acting as harmful pathogen may induce NLRP3
inflammasome signaling pathway activation and suppres-
sion of NLRP3 inflammasome may attenuate the effect,
which was consistent with the published reports [30, 31].
These results indicated that during the process of
combating airborne microorganisms, NLRP3 inflamma-
some served as pattern recognition receptor being activated
by a broad range of pathogen associated molecular patterns
and could trigger the activation of caspase-1, leading to the
maturation of IL-1β and IL-18, which exerted pro-
inflammatory effects in enhancing nasal polypogenesis
(Fig. 4). Along with the thorough research in the future,
NLRP3 inflammasome may be a novel molecular target in
the diagnosis and gene therapy of CRSwNP clinically.
Some limitations of our study should be interpreted.
First, relatively small sample size was included in this study,
and studies with large sample sizes and representative pop-
ulation are warranted to further clarify this finding. Second,
we only studied the role of NLRP3 in CRSwNP, and fully
detailed studies on the NLRP3 role in various phenotypes of
chronic rhinosinusitis involving chronic rhinosinusitis with-
out nasal polyps (CRSsNP) and chronic refractory rhinosi-
nusitis are needed to be performed so as to further clarify the
role of NLRP3 in the pathogenesis of chronic rhinosinusitis
in the future.
In conclusion, NLRP3 inflammasome played a piv-
otal role in the pathogenesis of CRSwNP, especially in
ECRSwNP. NLRP3 inflammasome signaling pathway
was augmented by LPS but suppressed by glyburide.
ACKNOWLEDGMENTS
This work was supported by Fujian Provincial Natu-
ral Science Foundation of China (No. 2010 J01215 and
No. 2015 J01302).
2051
COMPLIANCE WITH ETHICAL STANDARDS
This study was approved by the ethical committees of
Shanghai Jiao Tong University Affiliated Sixth People’s
Hospital and Fuzhou General Hospital, and an informed
consent was provided from every subject.
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