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1.
Cell Death Dis ; 15(5): 356, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38778059

ABSTRACT

IL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37+/ST2L+/CD206+ tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer.


Subject(s)
Interleukin-33 , Lung Neoplasms , Macrophages , NF-kappa B , rab GTP-Binding Proteins , Interleukin-33/metabolism , Interleukin-33/genetics , Humans , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , NF-kappa B/metabolism , Macrophages/metabolism , Macrophages/drug effects , Animals , rab GTP-Binding Proteins/metabolism , rab GTP-Binding Proteins/genetics , Mice , Feedback, Physiological , Cell Line, Tumor , Signal Transduction/drug effects , Mice, Inbred C57BL , Female
2.
Proc Natl Acad Sci U S A ; 121(22): e2310864121, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38781213

ABSTRACT

IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals and that single-nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production in innate lymphoid cells (ILCs) but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33's influence on IL-22-dependent antibacterial defense was dependent on housing conditions of the mice and mediated by IL-33's modulatory effect on the gut microbiota. Collectively, we provide insight into the bidirectional crosstalk between the innate immune system and the microbiota. We conclude that both genetic and environmental factors influence the gut microbiota, thereby impacting the efficacy of antibacterial immune defense and susceptibility to pneumonia.


Subject(s)
Immunity, Innate , Interleukin-1 Receptor-Like 1 Protein , Interleukin-22 , Interleukin-33 , Interleukins , Streptococcus pneumoniae , Animals , Interleukin-33/immunology , Interleukin-33/genetics , Interleukin-33/metabolism , Interleukins/metabolism , Interleukins/immunology , Interleukins/genetics , Mice , Streptococcus pneumoniae/immunology , Interleukin-1 Receptor-Like 1 Protein/metabolism , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/immunology , Humans , Mice, Knockout , Microbiota/immunology , Mice, Inbred C57BL , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/microbiology , Gastrointestinal Microbiome/immunology , Lymphocytes/immunology , Lymphocytes/metabolism , Polymorphism, Single Nucleotide
3.
Nutrients ; 16(8)2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38674885

ABSTRACT

The cellular and molecular mechanisms of atherosclerosis are still unclear. Type 2 innate lymphocytes (ILC2) exhibit anti-inflammatory properties and protect against atherosclerosis. This study aimed to elucidate the pathogenesis of atherosclerosis development using atherosclerosis model mice (ApoE KO mice) and mice deficient in IL-33 receptor ST2 (ApoEST2 DKO mice). Sixteen-week-old male ApoE KO and ApoEST2 DKO mice were subjected to an 8-week regimen of a high-fat, high-sucrose diet. Atherosclerotic foci were assessed histologically at the aortic valve ring. Chronic inflammation was assessed using flow cytometry and real-time polymerase chain reaction. In addition, saturated fatty acids (palmitic acid) and IL-33 were administered to human aortic endothelial cells (HAECs) to assess fatty acid metabolism. ApoEST2 DKO mice with attenuated ILC2 had significantly worse atherosclerosis than ApoE KO mice. The levels of saturated fatty acids, including palmitic acid, were significantly elevated in the arteries and serum of ApoEST2 DKO mice. Furthermore, on treating HAECs with saturated fatty acids with or without IL-33, the Oil Red O staining area significantly decreased in the IL-33-treated group compared to that in the non-treated group. IL-33 potentially prevented the accumulation of saturated fatty acids within atherosclerotic foci.


Subject(s)
Atherosclerosis , Fatty Acids , Interleukin-33 , Mice, Knockout , Animals , Interleukin-33/metabolism , Interleukin-33/genetics , Atherosclerosis/metabolism , Male , Mice , Fatty Acids/metabolism , Humans , Disease Models, Animal , Palmitic Acid/pharmacology , Apolipoproteins E/genetics , Apolipoproteins E/deficiency , Diet, High-Fat , Interleukin-1 Receptor-Like 1 Protein/metabolism , Interleukin-1 Receptor-Like 1 Protein/genetics , Endothelial Cells/metabolism , Mice, Knockout, ApoE , Lymphocytes/metabolism , Mice, Inbred C57BL , Aorta/metabolism , Aorta/pathology , Immunity, Innate
4.
APMIS ; 132(7): 515-525, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38566447

ABSTRACT

The ST2/IL-33 signaling pathway has an important role in the host inflammatory response. Here we aimed to study the association of ST2 and IL-33 polymorphisms with serum soluble (s) ST2 and IL-33 concentrations in healthy Finnish children and, in addition, their association with childhood asthma. In total, 146 children were followed from birth to the age 7 years for the development of asthma. Single-nucleotide polymorphisms (SNPs) in ST2 and IL-33 were determined, and associations of the SNP variants with serum levels of sST2 and IL-33 at age of 13 months and with recurrent wheezing and childhood asthma at 7 years of age were analyzed. Children with ST2 rs1041973 AC/AA genotypes had significantly lower level of serum sST2 (2453 pg/mL; IQR 2265) than those with CC genotype (5437 pg/mL; IQR 2575; p = < 0.0001). Similar difference was also observed with ST2 rs13408661. No differences were observed between subjects with studied IL-33 SNPs. Children who carried genetic variants of ST2 rs1041973 or rs13408661 seemed to have a higher risk of asthma. In contrast, children who carried genetic variants of IL-33 rs12551268 were less often diagnosed with asthma. Even though these SNPs seemed to associate with asthma, the differences were not statistically significant.


Subject(s)
Asthma , Genetic Predisposition to Disease , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33 , Polymorphism, Single Nucleotide , Humans , Asthma/genetics , Interleukin-33/genetics , Interleukin-33/blood , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/blood , Finland/epidemiology , Female , Male , Child , Child, Preschool , Prospective Studies , Infant , Infant, Newborn , Birth Cohort , Respiratory Sounds/genetics
5.
Nat Commun ; 15(1): 2707, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38548743

ABSTRACT

Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. Periodontal tissue is comprised of four different components, each with potential role in pathogenesis, however, most studies on immune responses focus on gingival tissue. Here, we present a modified ligature-induced periodontitis model in male mice to analyze the pathogenesis, which captures the complexity of periodontal tissue. We find that the inflammatory response in the peri-root tissues and the expression of IL-6 and RANKL by Thy-1.2- fibroblasts/stromal cells are prominent throughout the bone destruction phase, and present already at an early stage. The initiation phase is characterized by high levels of ST2 (encoded by Il1rl1) expression in the peri-root tissue, suggesting that the IL-33/ST2 axis is involved in the pathogenesis. Both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss in the acute phase of periodontitis, along with macrophage polarization towards a classically activated phenotype and increased neutrophil infiltration, indicating a protective role of the IL-33/ST2 axis in acute inflammation. Thus, our findings highlight the hidden role of the peri-root tissue and simultaneously advance our understanding of the etiology of periodontitis via implicating the IL-33/ST2 axis.


Subject(s)
Alveolar Bone Loss , Periodontitis , Animals , Male , Mice , Inflammation/metabolism , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-33/genetics
6.
JCI Insight ; 9(5)2024 Mar 08.
Article in English | MEDLINE | ID: mdl-38456508

ABSTRACT

IL-33 is a cytokine central to type 2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how expression is regulated is undefined. Here we show that increased IL33 expression occurs from multiple noncanonical promoters in human chronic obstructive pulmonary disease (COPD), and it facilitates production of alternatively spliced isoforms in airway cells. We found that phorbol 12-myristate 13-acetate (PMA) can activate IL33 promoters through protein kinase C in primary airway cells and lines. Transcription factor (TF) binding arrays combined with RNA interference identified activator protein (AP) TFs as regulators of baseline and induced IL33 promoter activity. ATAC-Seq and ChIP-PCR identified chromatin accessibility and differential TF binding as additional control points for transcription from noncanonical promoters. In support of a role for these TFs in COPD pathogenesis, we found that AP-2 (TFAP2A, TFAP2C) and AP-1 (FOS and JUN) family members are upregulated in human COPD specimens. This study implicates integrative and pioneer TFs in regulating IL33 promoters and alternative splicing in human airway basal cells. Our work reveals a potentially novel approach for targeting IL-33 in development of therapeutics for COPD.


Subject(s)
Interleukin-33 , Pulmonary Disease, Chronic Obstructive , Humans , Interleukin-33/genetics , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-jun/metabolism , Pulmonary Disease, Chronic Obstructive/genetics , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism
7.
BMC Ophthalmol ; 24(1): 144, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38553670

ABSTRACT

AIM: To elaborate the underlying mechanisms by which IL-1ß promote progression of Dry eye disease(DED) through effect on pyroptosis and apoptosis of corneal epithelial cells(CECs). METHODS: 400 mOsM solutions were used to establish the DED model (hCECs- DED). RT-qPCR was performed to measure IL-1ß mRNA and miR-146a-5p in CECs. Western blotting was performed to measure STAT3, GSDMD, NLRP3, and Caspase-1 levels. Cell counting kit-8 assay was adopted to check cell viability. Apoptosis was detected by flow cytometry. ELISAs were performed to determine IL-18, IL-33 and LDH. The luciferase test detects targeting relationships. RESULTS: After treatment with 400 mOsM solution, cell viability decreased and apoptosis increased. Compared with hCECs, IL-1ß was increased and miR-146a-5p was decreased in hCECs-DED. At the same time, GSDMD, NLRP3, Caspase-1, IL-18, IL-33 and LDH were significantly higher in hCECs-DED than in hCECs, while IL-1ß silencing reversed this effect. In addition, IL-1ß negatively regulated miR-146a-5p. MiR-146a-5p mimics eliminated the inhibition of hCECs-DED pyroptosis and apoptosis caused by IL-1ß silencing. At the same time, miR-146a-5p reduced STAT3 levels in hCECs. CONCLUSION: Highly expressed IL-1ß promoted pyroptosis and apoptosis of hCECs- DED through downregulated miR-146a-5p and inhibited STAT3.


Subject(s)
Dry Eye Syndromes , MicroRNAs , Humans , Pyroptosis , MicroRNAs/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Interleukin-18/genetics , Interleukin-18/metabolism , Interleukin-33/genetics , Down-Regulation , Apoptosis , Dry Eye Syndromes/genetics , Epithelial Cells/metabolism , Caspases/genetics , STAT3 Transcription Factor/genetics
8.
Lung ; 202(2): 127-137, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38502305

ABSTRACT

PURPOSE: The respiratory syncytial virus (RSV) is a common respiratory virus that causes acute lower respiratory tract infectious diseases, particularly in young children and older individuals. Activated leukocyte cell adhesion molecule (ALCAM) is a membrane glycoprotein expressed in various cell types, including epithelial cells, and is associated with inflammatory responses and various cancers. However, the precise role of ALCAM in RSV-induced airway inflammation remains unclear, and our study aimed to explore this gap in the literature. METHODS: C57BL/6 wild-type, ALCAM knockout mice and airway epithelial cells were infected with RSV and the expression of ALCAM and inflammatory cytokines were measured. We also conducted further experiments using Anti-ALCAM antibody and recombinant ALCAM in airway epithelial cells. RESULTS: The expression levels of ALCAM and inflammatory cytokines increased in both RSV-infected mice and airway epithelial cells. Interestingly, IL-33 expression was significantly reduced in ALCAM-knockdown cells compared to control cells following RSV infection. Anti-ALCAM antibody treatment also reduced IL-33 expression following RSV infection. Furthermore, the phosphorylation of ERK1/2, p38, and JNK was diminished in ALCAM-knockdown cells compared to control cells following RSV infection. Notably, in the control cells, inhibition of these pathways significantly decreased the expression of IL-33. In vivo study also confirmed a reduction in inflammation induced by RSV infection in ALCAM deficient mice compared to wild-type mice. CONCLUSION: These findings demonstrate that ALCAM contributes to RSV-induced airway inflammation at least partly by influencing IL-33 expression through mitogen-activated protein kinase signaling pathways. These results suggest that targeting ALCAM could be a potential therapeutic strategy for alleviating IL-33-associated lung diseases.


Subject(s)
Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Animals , Mice , Activated-Leukocyte Cell Adhesion Molecule/metabolism , Cytokines/metabolism , Inflammation/metabolism , Interleukin-33/genetics , Interleukin-33/metabolism , Lung/metabolism , MAP Kinase Signaling System , Mice, Inbred BALB C , Mice, Inbred C57BL , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus, Human/metabolism , Signal Transduction
9.
Biochem Pharmacol ; 223: 116163, 2024 May.
Article in English | MEDLINE | ID: mdl-38522555

ABSTRACT

Allergic contact dermatitis (ACD) is a common skin disease featured with skin inflammation and a mixed itch/pain sensation. The itch/pain causes the desire to scratch, affecting both physical and psychological aspects of patients. Nevertheless, the mechanisms underlying itch/pain sensation of ACD still remain elusive. Here, we found that oxidative stress and oxidation-related injury were remarkably increased in the inflamed skin of a mouse model of ACD. Reducing oxidative stress significantly attenuated itch/pain-related scratching, allokonesis and skin inflammation. RNA-Sequencing reveals oxidative stress contributes to a series of skin biological processes, including inflammation and immune response. Attenuating oxidative stress reduces overproduction of IL-1ß and IL-33, two critical cytokines involved in inflammation and pain/itch, in the inflamed skin of model mice. Exogenously injecting H2O2 into the neck skin of naïve mice triggered IL-33 overproduction in skin keratinocytes and induced scratching, which was reduced in mice deficient in IL-33 receptor ST2. ACD model mice showed remarkable neutrophil infiltration in the inflamed skin. Blocking neutrophil infiltration reduced oxidative stress and attenuated scratching and skin inflammation. Therefore, our study reveals a critical contribution of neutrophil-derived oxidative stress to skin inflammation and itch/pain-related scratching of ACD model mice via mechanisms involving the triggering of IL-33 overproduction in skin keratinocytes. Targeting skin oxidative stress may represent an effective therapy for ameliorating ACD.


Subject(s)
Dermatitis, Allergic Contact , Interleukin-33 , Humans , Animals , Mice , Interleukin-33/genetics , Cytokines , Hydrogen Peroxide/pharmacology , Neutrophils , Skin , Dermatitis, Allergic Contact/psychology , Pruritus/chemically induced , Disease Models, Animal , Inflammation , Pain
10.
J Allergy Clin Immunol ; 153(5): 1355-1368, 2024 May.
Article in English | MEDLINE | ID: mdl-38310974

ABSTRACT

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.


Subject(s)
Eosinophilic Esophagitis , Interleukin-13 , Interleukin-33 , Animals , Humans , Mice , Disease Models, Animal , Eosinophilic Esophagitis/immunology , Eosinophilic Esophagitis/genetics , Eosinophilic Esophagitis/pathology , Eosinophils/immunology , Esophageal Mucosa/pathology , Esophageal Mucosa/immunology , Esophagus/pathology , Esophagus/immunology , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/metabolism , Interleukin-13/genetics , Interleukin-13/immunology , Interleukin-13/metabolism , Interleukin-33/genetics , Interleukin-33/immunology , Interleukin-33/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic
11.
Int J Mol Sci ; 25(3)2024 Jan 23.
Article in English | MEDLINE | ID: mdl-38338680

ABSTRACT

Sepsis is a common life-threatening disease caused by dysregulated immune response and metabolic acidosis which lead to organ failure. An abnormal expression of aquaporins plays an important role in organ failure. Additionally, genetic variants in aquaporins impact on the outcome in sepsis. Thus, we investigated the polymorphism (rs17553719) and expression of aquaporin-3 (AQP3) and correlated these measurements with the survival of sepsis patients. Accordingly, we collected blood samples on several days (plus clinical data) from 265 sepsis patients who stayed in different ICUs in Germany. Serum plasma, DNA, and RNA were then separated to detect the promotor genotypes of AQP3 mRNA expression of AQP3 and several cytokines. The results showed that the homozygote CC genotype exhibited a significant decrease in 30-day survival (38.9%) compared to the CT (66.15%) and TT genotypes (76.3%) (p = 0.003). Moreover, AQP3 mRNA expression was significantly higher and nearly doubled in the CC compared to the CT (p = 0.0044) and TT genotypes (p = 0.018) on the day of study inclusion. This was accompanied by an increased IL-33 concentration in the CC genotype (day 0: p = 0.0026 and day 3: p = 0.008). In summary, the C allele of the AQP3 polymorphism (rs17553719) shows an association with increased AQP3 expression and IL-33 concentration accompanied by decreased survival in patients with sepsis.


Subject(s)
Aquaporins , Sepsis , Humans , Aquaporin 3/genetics , Aquaporins/genetics , Aquaporins/metabolism , Genotype , Interleukin-33/genetics , Interleukin-33/metabolism , RNA, Messenger/metabolism , Sepsis/genetics , Sepsis/metabolism
12.
Cell Cycle ; 23(2): 169-187, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38267823

ABSTRACT

IL-33 has been associated with pro- and anticancer functions in cancer. However, its role in pancreatic cancer metastasis remains unknown. This study aimed to explore the role of miR-548t-5p/IL-33 axis in the metastasis of pancreatic cancer. Luciferase activity assay, qRT-PCR, Western blot and ELISA were performed to prove whether IL-33 is the target of miR-548t-5p. In vivo metastasis assay and cellular transwell assay were performed to explore the role of miR-548t-5p/IL-33 axis in the invasion and metastasis of pancreatic cancer. Co-culture experiments and immunohistochemistry were performed to observe whether IL-33 affects cell invasion and metastasis dependent on the involvement of M2 macrophages. THP-1 cell induction experiment and flow cytometry were performed to explore the effect of IL-33 on macrophage polarization. CCK-8, colony formation, cell apoptosis, cell cycle, cell wound healing and transwell assay were performed to investigate the effect of IL-33 induced M2 macrophages on cell malignant biological behavior by coculturing pancreatic cancer cells with the conditioned medium (CM) from macrophages. We found that miR-548t-5p regulated the expression and secretion of IL-33 in pancreatic cancer cells by directly targeting IL-33 mRNA. IL-33 secreted by cancer cells promoted the recruitment and activation of macrophages to a M2-like phenotype. In turn, IL-33 induced M2 macrophages promoted the migration and invasion of cancer cells. Moreover, IL-33 affected pancreatic cancer cell invasion dependent on the involvement of M2 macrophages in the co-culture system. Thus, our study suggested that manipulation of this IL-33-dependent crosstalk has a therapeutic potential for the treatment of pancreatic cancer metastasis.


Subject(s)
Carcinoma, Pancreatic Ductal , Gene Expression Regulation, Neoplastic , Interleukin-33 , Macrophages , MicroRNAs , Pancreatic Neoplasms , MicroRNAs/genetics , MicroRNAs/metabolism , Humans , Interleukin-33/metabolism , Interleukin-33/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Macrophages/metabolism , Animals , Cell Line, Tumor , Neoplasm Metastasis , Cell Movement/genetics , Neoplasm Invasiveness , Mice , Apoptosis/genetics , Coculture Techniques , Mice, Nude , Cell Proliferation/genetics , THP-1 Cells
13.
Biol Reprod ; 110(5): 924-935, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38271626

ABSTRACT

It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of interleukin 33 or interleukin 33 Knock-out (KO) (Il33-/-) not only inhibited NFκB activity in ovaries, but it also altered expression of two key genes, i.e., reduction in proinflammatory interleukin6 (IL6) expression, and a surge of potential autophagy-inhibitory mammalian target of rapamycin (mTOR) expression in atretic follicles. By contrast, apoptosis and other genes, such as interleukin1ß (IL1ß) were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the interleukin 33-suppression of tumorigenicity 2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy and (2) up-regulated expression of proinflammatory IL6.


Subject(s)
Follicular Atresia , Granulosa Cells , Interleukin-33 , NF-kappa B , Ovarian Follicle , Female , Animals , Granulosa Cells/metabolism , Granulosa Cells/drug effects , Mice , NF-kappa B/metabolism , Follicular Atresia/metabolism , Ovarian Follicle/metabolism , Interleukin-33/metabolism , Interleukin-33/genetics , Signal Transduction , Mice, Knockout , Autophagy/physiology
14.
Infect Immun ; 92(3): e0039523, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38294241

ABSTRACT

HpARI is an immunomodulatory protein secreted by the intestinal nematode Heligmosomoides polygyrus bakeri, which binds and blocks IL-33. Here, we find that the H. polygyrus bakeri genome contains three HpARI family members and that these have different effects on IL-33-dependent responses in vitro and in vivo, with HpARI1+2 suppressing and HpARI3 amplifying these responses. All HpARIs have sub-nanomolar affinity for mouse IL-33; however, HpARI3 does not block IL-33-ST2 interactions. Instead, HpARI3 stabilizes IL-33, increasing the half-life of the cytokine and amplifying responses to it in vivo. Together, these data show that H. polygyrus bakeri secretes a family of HpARI proteins with both overlapping and distinct functions, comprising a complex immunomodulatory arsenal of host-targeted proteins.


Subject(s)
Nematospiroides dubius , Strongylida Infections , Mice , Animals , Interleukin-33/genetics , Cytokines , Immunomodulation , Immunity
15.
Anticancer Agents Med Chem ; 24(5): 389-397, 2024.
Article in English | MEDLINE | ID: mdl-38192141

ABSTRACT

BACKGROUND: Interleukin (IL)-33 is highly expressed in glioblastoma (GBM) and promotes tumor progression. Targeting IL-33 may be an effective strategy for the treatment of GBM. Dexamethasone (DEX) is a controversial drug routinely used clinically in GBM therapy. Whether DEX has an effect on IL-33 is unknown. This study aimed to investigate the effect of DEX on IL-33 and the molecular mechanisms involved. METHODS: U87MG cells were induced by tumor necrosis factor (TNF)-α to express IL-33 and then treated with DEX. The mRNA levels of IL-33, NF-κB p65, ERK1/2, and p38 were determined by real-time quantitative PCR. The expression of IL-33, IkBα (a specific inhibitor of NF-κB) and MKP-1 (a negative regulator of MAPK), as well as the phosphorylation of NF-κB, ERK1/2 and p38 MAPK, were detected by Western blotting. The secretion of IL-33 was measured by ELISA. The proliferation, migration and invasion of U87MG cells were detected by CCK8 and transwell assays, respectively. RESULTS: DEX significantly reduced TNF-α-induced production of IL-33 in U87MG cells, which was dependent on inhibiting the activation of the NF-κB, ERK1/2 and p38 MAPK signaling pathways, and was accompanied by the increased expression of IkBα but not MKP-1. Furthermore, the proliferation, migration and invasion of U87MG cells exacerbated by IL-33 were suppressed by DEX. CONCLUSION: DEX inhibited the production and tumor-promoting function of IL-33. Whether DEX can benefit GBM patients remains controversial. Our results suggest that GBM patients with high IL-33 expression may benefit from DEX treatment and deserve further investigation.


Subject(s)
Glioblastoma , NF-kappa B , Humans , NF-kappa B/metabolism , MAP Kinase Signaling System , Glioblastoma/drug therapy , Interleukin-33/genetics , Interleukin-33/metabolism , Signal Transduction , Tumor Necrosis Factor-alpha , Dexamethasone/pharmacology , p38 Mitogen-Activated Protein Kinases , Phenotype
16.
EMBO Mol Med ; 16(2): 251-266, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38238529

ABSTRACT

Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.


Subject(s)
Peritoneal Neoplasms , Stomach Neoplasms , Humans , Animals , Mice , Stomach Neoplasms/therapy , Peritoneal Neoplasms/therapy , Peritoneal Neoplasms/metabolism , Peritoneal Neoplasms/pathology , Interleukin-33/genetics , Interleukin-33/therapeutic use , Interleukin-33/metabolism , Macrophages , Immunotherapy , Tumor Microenvironment , Cell Line, Tumor
18.
Nat Immunol ; 25(2): 256-267, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38172258

ABSTRACT

The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases.


Subject(s)
Interleukin-1 Receptor-Like 1 Protein , Interleukin-33 , Humans , Animals , Mice , Interleukin-33/genetics , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/metabolism , Alarmins , T-Lymphocyte Subsets/metabolism , Antiviral Agents
19.
Immunity ; 57(1): 141-152.e5, 2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38091996

ABSTRACT

Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.


Subject(s)
Adipose Tissue, Brown , Leptin , Animals , Humans , Mice , Adipose Tissue, Brown/innervation , Adipose Tissue, Brown/metabolism , Body Weight , Energy Metabolism/physiology , Interleukin-33/genetics , Interleukin-33/metabolism , Obesity/metabolism , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Thermogenesis/physiology
20.
Am J Physiol Lung Cell Mol Physiol ; 326(1): L65-L70, 2024 01 01.
Article in English | MEDLINE | ID: mdl-38050688

ABSTRACT

IL-33 and IL-1RL1 are well-replicated asthma genes that act in a single pathway toward type-2 immune responses. IL-33 is expressed by basal epithelial cells, and the release of IL-33 upon epithelial damage can activate innate lymphoid cells, T helper-2 cells, basophilic granulocytes, and mast cells through a receptor complex containing IL-1RL1. However, it is unknown how bronchial epithelial cells respond to IL-33, and whether this response is increased in the disease. We aimed to characterize the IL-33-driven transcriptomic changes in cultured primary bronchial epithelial cells from patients with asthma and healthy controls. Primary bronchial epithelial cells (PBECs) were obtained by bronchial brushing from six healthy control for air-liquid interface (ALI) cultures, whereas we selected eight healthy controls and seven patients with asthma for epithelial organoid cultures. We then stimulated the cultures for 24 h with recombinant IL-33 (rhIL33) at various concentrations with 1, 10, and 50 ng/mL for the ALI cultures and 20 ng/mL and 100 ng/mL for the organoid cultures, followed by RNA-sequencing and differential gene expression analysis. We did not detect any genome-wide significant differentially expressed genes after stimulation of PBECs with IL-33, irrespective of growth in three-dimensional (3-D) epithelial organoids or after differentiation in ALI cultures. These results were identical between PBECs obtained from patients with asthma or from healthy control subjects. We detected very low levels of IL-1RL1 gene expression in these airway epithelial cell cultures. We conclude that bronchial epithelial cells do not have a transcriptional response to IL-33, independent of their differentiation state. Hence, the airway epithelium acts as a source of IL-33 but does not seem to contribute to the response upon release of the alarmin after epithelial damage.NEW & NOTEWORTHY The IL-33/IL-1RL1 pathway stands as a formidable genetic predisposition for asthma, with ongoing clinical developments of various drugs designed to mitigate its influence in patients with asthma. The absence of a transcriptomic reaction to IL-33 within the bronchial epithelium holds significance in the pursuit of identifying biomarkers that can aid in pinpointing those individuals who would derive the greatest benefit from therapies targeting the IL-33 pathway.


Subject(s)
Asthma , Immunity, Innate , Humans , Interleukin-33/genetics , Lymphocytes , Asthma/metabolism , Bronchi/metabolism , Epithelial Cells/metabolism , Cells, Cultured
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