Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.

1.
Morita
H
,
Matsumoto
K
,
Saito
H
.
Biologics for allergic and immunologic diseases
.
J Allergy Clin Immunol
.
2022
;
150
(
4
):
766
77
.
2.
Busse
WW
,
Viswanathan
R
.
What has been learned by cytokine targeting of asthma
.
J Allergy Clin Immunol
.
2022
;
150
(
2
):
235
49
.
3.
Kabata
H
,
Moro
K
,
Koyasu
S
.
The group 2 Innate Lymphoid Cell (ILC2) regulatory network and its underlying mechanisms
.
Immunol Rev
.
2018
;
286
(
1
):
37
52
.
4.
Orimo
K
,
Saito
H
,
Matsumoto
K
,
Morita
H
.
Innate lymphoid cells in the airways: their functions and regulators
.
Allergy Asthma Immunol Res
.
2020
;
12
(
3
):
381
98
.
5.
Orimo
K
,
Tamari
M
,
Saito
H
,
Matsumoto
K
,
Nakae
S
,
Morita
H
.
Characteristics of tissue-resident ILCs and their potential as therapeutic targets in mucosal and skin inflammatory diseases
.
Allergy
.
2021
;
76
(
11
):
3332
48
.
6.
Tanaka
K
,
Ogawa
K
,
Sugamura
K
,
Nakamura
M
,
Takano
S
,
Nagata
K
.
Cutting edge: differential production of prostaglandin D2 by human helper T cell subsets
.
J Immunol
.
2000
;
164
(
5
):
2277
80
.
7.
Hirata
M
,
Kakizuka
A
,
Aizawa
M
,
Ushikubi
F
,
Narumiya
S
.
Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene
.
Proc Natl Acad Sci U S A
.
1994
;
91
(
23
):
11192
6
.
8.
Nagata
K
,
Hirai
H
,
Tanaka
K
,
Ogawa
K
,
Aso
T
,
Sugamura
K
, et al
.
CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s)
.
FEBS Lett
.
1999
;
459
(
2
):
195
9
.
9.
Matsuoka
T
,
Hirata
M
,
Tanaka
H
,
Takahashi
Y
,
Murata
T
,
Kabashima
K
, et al
.
Prostaglandin D2 as a mediator of allergic asthma
.
Science
.
2000
;
287
(
5460
):
2013
7
.
10.
Hammad
H
,
Kool
M
,
Soullié
T
,
Narumiya
S
,
Trottein
F
,
Hoogsteden
HC
, et al
.
Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells
.
J Exp Med
.
2007
;
204
(
2
):
357
67
.
11.
Kostenis
E
,
Ulven
T
.
Emerging roles of DP and CRTH2 in allergic inflammation
.
Trends Mol Med
.
2006
;
12
(
4
):
148
58
.
12.
Domingo
C
,
Palomares
O
,
Sandham
DA
,
Erpenbeck
VJ
,
Altman
P
.
The prostaglandin D(2) receptor 2 pathway in asthma: a key player in airway inflammation
.
Respir Res
.
2018
;
19
(
1
):
189
.
13.
Fajt
ML
,
Gelhaus
SL
,
Freeman
B
,
Uvalle
CE
,
Trudeau
JB
,
Holguin
F
, et al
.
Prostaglandin D₂ pathway upregulation: relation to asthma severity, control, and TH2 inflammation
.
J Allergy Clin Immunol
.
2013
;
131
(
6
):
1504
12
.
14.
Palikhe
NS
,
Laratta
C
,
Nahirney
D
,
Vethanayagam
D
,
Bhutani
M
,
Vliagoftis
H
, et al
.
Elevated levels of circulating CD4(+) CRTh2(+) T cells characterize severe asthma
.
Clin Exp Allergy
.
2016
;
46
(
6
):
825
36
.
15.
Huang
JL
,
Gao
PS
,
Mathias
RA
,
Yao
TC
,
Chen
LC
,
Kuo
ML
, et al
.
Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability
.
Hum Mol Genet
.
2004
;
13
(
21
):
2691
7
.
16.
Uller
L
,
Mathiesen
JM
,
Alenmyr
L
,
Korsgren
M
,
Ulven
T
,
Högberg
T
, et al
.
Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation
.
Respir Res
.
2007
;
8
(
1
):
16
.
17.
Lukacs
NW
,
Berlin
AA
,
Franz-Bacon
K
,
Sásik
R
,
Sprague
LJ
,
Ly
TW
, et al
.
CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation
.
Am J Physiol Lung Cell Mol Physiol
.
2008
;
295
(
5
):
L767
79
.
18.
Crosignani
S
,
Jorand-Lebrun
C
,
Page
P
,
Campbell
G
,
Colovray
V
,
Missotten
M
, et al
.
Optimization of the central core of indolinone-acetic acid-based CRTH2 (DP2) receptor antagonists
.
ACS Med Chem Lett
.
2011
;
2
(
8
):
644
9
.
19.
Tasaki
M
,
Kobayashi
M
,
Tenda
Y
,
Tsujimoto
S
,
Nakazato
S
,
Numazaki
M
, et al
.
Inhibition of antigen-induced airway inflammation and hyperresponsiveness in Guinea pigs by a selective antagonist of “chemoattractant receptor homologous molecule expressed on Th2 cells” (CRTH2)
.
Eur J Pharm Sci
.
2013
;
49
(
3
):
434
40
.
20.
Nishikawa-Shimono
R
,
Sekiguchi
Y
,
Kawamura
M
,
Wakasugi
D
,
Kawanishi
M
,
Watanabe
K
, et al
.
Isoquinoline derivatives as potent, selective, and orally active CRTH2 antagonists
.
Chem Pharm Bull
.
2014
;
62
(
6
):
528
37
.
21.
Gervais
FG
,
Sawyer
N
,
Stocco
R
,
Hamel
M
,
Krawczyk
C
,
Sillaots
S
, et al
.
Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist
.
Mol Pharmacol
.
2011
;
79
(
1
):
69
76
.
22.
Kaila
N
,
Huang
A
,
Moretto
A
,
Follows
B
,
Janz
K
,
Lowe
M
, et al
.
Diazine indole acetic acids as potent, selective, and orally bioavailable antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases
.
J Med Chem
.
2012
;
55
(
11
):
5088
109
.
23.
Ortega
H
,
Fitzgerald
M
,
Raghupathi
K
,
Tompkins
CA
,
Shen
J
,
Dittrich
K
, et al
.
A phase 2 study to evaluate the safety, efficacy and pharmacokinetics of DP2 antagonist GB001 and to explore biomarkers of airway inflammation in mild-to-moderate asthma
.
Clin Exp Allergy
.
2020
;
50
(
2
):
189
97
.
24.
Kuna
P
,
Bjermer
L
,
Tornling
G
.
Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma
.
Drug Des Devel Ther
.
2016
;
10
:
2759
70
.
25.
Erpenbeck
VJ
,
Popov
TA
,
Miller
D
,
Weinstein
SF
,
Spector
S
,
Magnusson
B
, et al
.
The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma
.
Pulm Pharmacol Ther
.
2016
;
39
:
54
63
.
26.
Bateman
ED
,
Guerreros
AG
,
Brockhaus
F
,
Holzhauer
B
,
Pethe
A
,
Kay
RA
, et al
.
Fevipiprant, an oral prostaglandin DP(2) receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids
.
Eur Respir J
.
2017
;
50
(
2
):
1700670
.
27.
Barnes
N
,
Pavord
I
,
Chuchalin
A
,
Bell
J
,
Hunter
M
,
Lewis
T
, et al
.
A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma
.
Clin Exp Allergy
.
2012
;
42
(
1
):
38
48
.
28.
Singh
D
,
Cadden
P
,
Hunter
M
,
Pearce Collins
L
,
Perkins
M
,
Pettipher
R
, et al
.
Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459
.
Eur Respir J
.
2013
;
41
(
1
):
46
52
.
29.
Pettipher
R
,
Hunter
MG
,
Perkins
CM
,
Collins
LP
,
Lewis
T
,
Baillet
M
, et al
.
Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459
.
Allergy
.
2014
;
69
(
9
):
1223
32
.
30.
Diamant
Z
,
Sidharta
PN
,
Singh
D
,
O'Connor
BJ
,
Zuiker
R
,
Leaker
BR
, et al
.
Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics
.
Clin Exp Allergy
.
2014
;
44
(
8
):
1044
52
.
31.
Busse
WW
,
Wenzel
SE
,
Meltzer
EO
,
Kerwin
EM
,
Liu
MC
,
Zhang
N
, et al
.
Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients
.
J Allergy Clin Immunol
.
2013
;
131
(
2
):
339
45
.
32.
Chang
JE
,
Doherty
TA
,
Baum
R
,
Broide
D
.
Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis
.
J Allergy Clin Immunol
.
2014
;
133
(
3
):
899
901.e3
.
33.
Xue
L
,
Salimi
M
,
Panse
I
,
Mjösberg
JM
,
McKenzie
AN
,
Spits
H
, et al
.
Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells
.
J Allergy Clin Immunol
.
2014
;
133
(
4
):
1184
94
.
34.
Wojno
ED
,
Monticelli
LA
,
Tran
SV
,
Alenghat
T
,
Osborne
LC
,
Thome
JJ
, et al
.
The prostaglandin D₂ receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung
.
Mucosal Immunol
.
2015
;
8
(
6
):
1313
23
.
35.
Maric
J
,
Ravindran
A
,
Mazzurana
L
,
Van Acker
A
,
Rao
A
,
Kokkinou
E
, et al
.
Cytokine-induced endogenous production of prostaglandin D(2) is essential for human group 2 innate lymphoid cell activation
.
J Allergy Clin Immunol
.
2019
;
143
(
6
):
2202
14.e5
.
36.
Huang
T
,
Hazen
M
,
Shang
Y
,
Zhou
M
,
Wu
X
,
Yan
D
, et al
.
Depletion of major pathogenic cells in asthma by targeting CRTh2
.
JCI Insight
.
2016
;
1
(
7
):
e86689
.
37.
Takeda
K
,
Hamelmann
E
,
Joetham
A
,
Shultz
LD
,
Larsen
GL
,
Irvin
CG
, et al
.
Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice
.
J Exp Med
.
1997
;
186
(
3
):
449
54
.
38.
Williams
CM
,
Galli
SJ
.
Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice
.
J Exp Med
.
2000
;
192
(
3
):
455
62
.
39.
Mayr
SI
,
Zuberi
RI
,
Zhang
M
,
de Sousa-Hitzler
J
,
Ngo
K
,
Kuwabara
Y
, et al
.
IgE-dependent mast cell activation potentiates airway responses in murine asthma models
.
J Immunol
.
2002
;
169
(
4
):
2061
8
.
40.
Chevalier
E
,
Stock
J
,
Fisher
T
,
Dupont
M
,
Fric
M
,
Fargeau
H
, et al
.
Cutting edge: chemoattractant receptor-homologous molecule expressed on Th2 cells plays a restricting role on IL-5 production and eosinophil recruitment
.
J Immunol
.
2005
;
175
(
4
):
2056
60
.
41.
Kagawa
S
,
Fukunaga
K
,
Oguma
T
,
Suzuki
Y
,
Shiomi
T
,
Sayama
K
, et al
.
Role of prostaglandin D2 receptor CRTH2 in sustained eosinophil accumulation in the airways of mice with chronic asthma
.
Int Arch Allergy Immunol
.
2011
;
155
(
Suppl 1
):
6
11
.
42.
Shiraishi
Y
,
Asano
K
,
Niimi
K
,
Fukunaga
K
,
Wakaki
M
,
Kagyo
J
, et al
.
Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation
.
J Immunol
.
2008
;
180
(
1
):
541
9
.
43.
Satoh
T
,
Moroi
R
,
Aritake
K
,
Urade
Y
,
Kanai
Y
,
Sumi
K
, et al
.
Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor
.
J Immunol
.
2006
;
177
(
4
):
2621
9
.
44.
Oboki
K
,
Ohno
T
,
Kajiwara
N
,
Arae
K
,
Morita
H
,
Ishii
A
, et al
.
IL-33 is a crucial amplifier of innate rather than acquired immunity
.
Proc Natl Acad Sci U S A
.
2010
;
107
(
43
):
18581
6
.
45.
Tsuchiya
K
,
Siddiqui
S
,
Risse
PA
,
Hirota
N
,
Martin
JG
.
The presence of LPS in OVA inhalations affects airway inflammation and AHR but not remodeling in a rodent model of asthma
.
Am J Physiol Lung Cell Mol Physiol
.
2012
;
303
(
1
):
L54
63
.
46.
Orimo
K
,
Tamari
M
,
Takeda
T
,
Kubo
T
,
Rückert
B
,
Motomura
K
, et al
.
Direct platelet adhesion potentiates group 2 innate lymphoid cell functions
.
Allergy
.
2022
;
77
(
3
):
843
55
.
47.
Moro
K
,
Ealey
KN
,
Kabata
H
,
Koyasu
S
.
Isolation and analysis of group 2 innate lymphoid cells in mice
.
Nat Protoc
.
2015
;
10
(
5
):
792
806
.
48.
Brewer
JM
,
Conacher
M
,
Hunter
CA
,
Mohrs
M
,
Brombacher
F
,
Alexander
J
.
Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4- or IL-13-mediated signaling
.
J Immunol
.
1999
;
163
(
12
):
6448
54
.
49.
McKee
AS
,
Munks
MW
,
MacLeod
MK
,
Fleenor
CJ
,
Van Rooijen
N
,
Kappler
JW
, et al
.
Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity
.
J Immunol
.
2009
;
183
(
7
):
4403
14
.
50.
Kool
M
,
Pétrilli
V
,
De Smedt
T
,
Rolaz
A
,
Hammad
H
,
van Nimwegen
M
, et al
.
Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome
.
J Immunol
.
2008
;
181
(
6
):
3755
9
.
51.
Eisenbarth
SC
,
Colegio
OR
,
O'Connor
W
,
Sutterwala
FS
,
Flavell
RA
.
Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants
.
Nature
.
2008
;
453
(
7198
):
1122
6
.
52.
Li
H
,
Willingham
SB
,
Ting
JP
,
Re
F
.
Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3
.
J Immunol
.
2008
;
181
(
1
):
17
21
.
53.
Kool
M
,
Soullié
T
,
van Nimwegen
M
,
Willart
MA
,
Muskens
F
,
Jung
S
, et al
.
Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells
.
J Exp Med
.
2008
;
205
(
4
):
869
82
.
54.
Rose
WA
2nd
,
Okragly
AJ
,
Patel
CN
,
Benschop
RJ
.
IL-33 released by alum is responsible for early cytokine production and has adjuvant properties
.
Sci Rep
.
2015
;
5
:
13146
.
55.
Ohno
T
,
Morita
H
,
Arae
K
,
Matsumoto
K
,
Nakae
S
.
Interleukin-33 in allergy
.
Allergy
.
2012
;
67
(
10
):
1203
14
.
56.
Baba
Y
,
Nishida
K
,
Fujii
Y
,
Hirano
T
,
Hikida
M
,
Kurosaki
T
.
Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses
.
Nat Immunol
.
2008
;
9
(
1
):
81
8
.
57.
Boehme
SA
,
Franz-Bacon
K
,
Chen
EP
,
Ly
TW
,
Kawakami
Y
,
Bacon
KB
.
Murine bone marrow-derived mast cells express chemoattractant receptor-homologous molecule expressed on T-helper class 2 cells (CRTh2)
.
Int Immunol
.
2009
;
21
(
6
):
621
32
.
58.
Moon
TC
,
Campos-Alberto
E
,
Yoshimura
T
,
Bredo
G
,
Rieger
AM
,
Puttagunta
L
, et al
.
Expression of DP2 (CRTh2), a prostaglandin D₂ receptor, in human mast cells
.
PLoS One
.
2014
;
9
(
9
):
e108595
.
59.
Christianson
CA
,
Goplen
NP
,
Zafar
I
,
Irvin
C
,
Good
JT
Jr
,
Rollins
DR
, et al
.
Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33
.
J Allergy Clin Immunol
.
2015
;
136
(
1
):
59
68.e14
.
60.
Halim
TY
,
Krauss
RH
,
Sun
AC
,
Takei
F
.
Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation
.
Immunity
.
2012
;
36
(
3
):
451
63
.
61.
Petersen
BC
,
Budelsky
AL
,
Baptist
AP
,
Schaller
MA
,
Lukacs
NW
.
Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology
.
Nat Med
.
2012
;
18
(
5
):
751
8
.
62.
Morita
H
,
Arae
K
,
Unno
H
,
Miyauchi
K
,
Toyama
S
,
Nambu
A
, et al
.
An interleukin-33-mast cell-interleukin-2 Axis suppresses papain-induced allergic inflammation by promoting regulatory T cell numbers
.
Immunity
.
2015
;
43
(
1
):
175
86
.
63.
Unno
H
,
Arae
K
,
Matsuda
A
,
Ikutani
M
,
Tamari
M
,
Motomura
K
, et al
.
Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia
.
Biochem Biophys Res Commun
.
2020
;
533
(
3
):
493
500
.
64.
Arae
K
,
Ikutani
M
,
Horiguchi
K
,
Yamaguchi
S
,
Okada
Y
,
Sugiyama
H
, et al
.
Interleukin-33 and thymic stromal lymphopoietin, but not interleukin-25, are crucial for development of airway eosinophilia induced by chitin
.
Sci Rep
.
2021
;
11
(
1
):
5913
.
65.
Saito
K
,
Orimo
K
,
Kubo
T
,
Tamari
M
,
Yamada
A
,
Motomura
K
, et al
.
Laundry detergents and surfactants induced eosinophilic airway inflammation by increasing IL-33 expression and activating ILC2s
.
Allergy
.
2023
;
78
(
7
):
1878
92
.
66.
Shimokawa
C
,
Kanaya
T
,
Hachisuka
M
,
Ishiwata
K
,
Hisaeda
H
,
Kurashima
Y
, et al
.
Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections
.
Immunity
.
2017
;
46
(
5
):
863
74.e4
.
67.
Burton
OT
,
Medina Tamayo
J
,
Stranks
AJ
,
Miller
S
,
Koleoglou
KJ
,
Weinberg
EO
, et al
.
IgE promotes type 2 innate lymphoid cells in murine food allergy
.
Clin Exp Allergy
.
2018
;
48
(
3
):
288
96
.
68.
Thio
CL
,
Lai
AC
,
Ting
YT
,
Chi
PY
,
Chang
YJ
.
The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function
.
Cell Rep
.
2022
;
40
(
13
):
111437
.
69.
Moretti
S
,
Renga
G
,
Oikonomou
V
,
Galosi
C
,
Pariano
M
,
Iannitti
RG
, et al
.
A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis
.
Nat Commun
.
2017
;
8
:
14017
.
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