TY - JOUR
T1 - Interleukin 33 Triggers Early Eosinophil-Dependent Events Leading to Metaplasia in a Chronic Model of Gastritis-Prone Mice
AU - De Salvo, Carlo
AU - Pastorelli, Luca
AU - Petersen, Christine P.
AU - Buttò, Ludovica F.
AU - Buela, Kristine Ann
AU - Omenetti, Sara
AU - Locovei, Silviu A.
AU - Ray, Shuvra
AU - Friedman, Hannah R.
AU - Duijser, Jacob
AU - Xin, Wei
AU - Osme, Abdullah
AU - Cominelli, Fabio
AU - Mahabeleshwar, Ganapati H.
AU - Mills, Jason C.
AU - Goldenring, James R.
AU - Pizarro, Theresa T.
N1 - Funding Information:
Funding This work was supported by grants from the National Institutes of Health: DK056762, DK091222, DK042191, CA150964 Pilot & Feasibility Award (T.T.P.), DK071590 (J.R.G.), DK105129 (J.C.M.), a National Research Service Award F31 Predoctoral Fellowship DK104600 (C.P.P.), an Institutional T32 Fellowship from DK083251 (S.L.), as well as Cores from the Cleveland Silvio O. Conte Digestive Diseases Research Core Center (DK097948). Other funding sources include the DeGregorio Family Foundation (T.T.P.), the Department of Veterans Affairs: I01BX000930 (J.R.G.), the Crohn's & Colitis Foundation: RFA326877, CDA581292 (C.D.S.), RFA410354 (K.A.B), and SRFA592800 (H.R.F.), the American Gastroenterological Association: Eli & Edythe Broad Student Research Fellowship Award (H.R.F., J.D.), and the Italian Society of Gastroenterology (L.P.).
Funding Information:
Funding This work was supported by grants from the National Institutes of Health: DK056762, DK091222, DK042191, CA150964 Pilot & Feasibility Award (T.T.P.), DK071590 (J.R.G.), DK105129 (J.C.M.), a National Research Service Award F31 Predoctoral Fellowship DK104600 (C.P.P.), an Institutional T32 Fellowship from DK083251 (S.L.), as well as Cores from the Cleveland Silvio O. Conte Digestive Diseases Research Core Center (DK097948). Other funding sources include the DeGregorio Family Foundation (T.T.P.), the Department of Veterans Affairs: I01BX000930 (J.R.G.), the Crohn’s & Colitis Foundation: RFA326877, CDA581292 (C.D.S.), RFA410354 (K.A.B), and SRFA592800 (H.R.F.), the American Gastroenterological Association: Eli & Edythe Broad Student Research Fellowship Award (H.R.F., J.D.), and the Italian Society of Gastroenterology (L.P.).
Publisher Copyright:
© 2021 AGA Institute
PY - 2021/1
Y1 - 2021/1
N2 - Background & Aims: Interleukin (IL)33/IL1F11 is an important mediator for the development of type 2 T-helper cell (Th2)–driven inflammatory disorders and has also been implicated in the pathogenesis of gastrointestinal (GI)-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL33’s potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice. Methods: SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL33 and its receptor, ST2/IL1R4, were characterized in corpus tissues, and activation and neutralization studies were both performed targeting the IL33/ST2 axis. Dissection of immune pathways leading to metaplasia was evaluated, including eosinophil depletion studies using anti-IL5/anti-CCR3 treatment. Results: Progressive gastritis and, ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR but could be moderately induced with exogenous, recombinant IL33. Robust peripheral (bone marrow) expansion of eosinophils and local recruitment of both eosinophils and IL33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL33 blockade did not affect bone marrow-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL33-producing M2 macrophages and SPEM in SAMP. Conclusions: IL33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for preneoplastic conditions of the GI tract.
AB - Background & Aims: Interleukin (IL)33/IL1F11 is an important mediator for the development of type 2 T-helper cell (Th2)–driven inflammatory disorders and has also been implicated in the pathogenesis of gastrointestinal (GI)-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL33’s potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice. Methods: SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL33 and its receptor, ST2/IL1R4, were characterized in corpus tissues, and activation and neutralization studies were both performed targeting the IL33/ST2 axis. Dissection of immune pathways leading to metaplasia was evaluated, including eosinophil depletion studies using anti-IL5/anti-CCR3 treatment. Results: Progressive gastritis and, ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR but could be moderately induced with exogenous, recombinant IL33. Robust peripheral (bone marrow) expansion of eosinophils and local recruitment of both eosinophils and IL33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL33 blockade did not affect bone marrow-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL33-producing M2 macrophages and SPEM in SAMP. Conclusions: IL33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for preneoplastic conditions of the GI tract.
KW - Gastric Cancer
KW - IL-33/ST2 Axis
KW - M2 Macrophages
KW - SPEM/Intestinalized SPEM
UR - http://www.scopus.com/inward/record.url?scp=85097681831&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.09.040
DO - 10.1053/j.gastro.2020.09.040
M3 - Article
C2 - 33010253
AN - SCOPUS:85097681831
VL - 160
SP - 302-316.e7
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 1
ER -