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1.
J Ethnopharmacol ; 282: 114581, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34464697

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The diterpenoids extracted from Euphorbia kansui S.L. Liou ex S.B.Ho, Euphorbia fischeriana Steud. have good antitumor effects. Jolkinolide B has anti-breast cancer effect, but it is unclear whether it has different therapeutic effects between luminal A subtype and luminal B subtype breast cancer. AIM OF THE STUDY: This study investigated the Jolkinolide B has different therapeutic, important targets and pathways effects between luminal A subtype and luminal B subtype breast cancer. MATERIALS AND METHODS: We used bioinformatics to predict the biological process and molecular mechanism of Jolkinolide B in treating two types of breast cancer. Then, in vitro, cultured MCF-7 cells and BT-474 cells were divided into control group, PI3K inhibitor + control group, Jolkinolide B group and PI3K inhibitor + Jolkinolide B group. The CCK-8 assay, Flow cytometric analysis and Transwell cell migration assay was used to detect the cell proliferation, apoptosis, and migration in each group, respectively. ELISA was used to measure the content of Akt and phosphorylated Akt (p-Akt) in cell lysis buffer. RESULTS: Compared to luminal A breast cancer, Jolkinolide B had more targets, proliferation, migration processes and KEGG pathways when treating luminal B subtype breast cancer. Jolkinolide B significantly prolonged the survival time of luminal B subtype breast cancer patients. Compared to the control group, the cell proliferation absorbance value (A value) and migration number of the two kinds of breast cancer cells in the Jolkinolide B group were decreased (P < 0.01, n = 6), and the number of apoptotic cells was increased (P < 0.01, n = 6). Compared to the Jolkinolide B group, the A value and migration number of the two types of breast cancer cells were significantly decreased in the PI3K inhibitor + Jolkinolide B group (P < 0.01, n = 6), and the number of apoptotic cells was significantly increased (P < 0.01, n = 6). In addition, compared to MCF-7 cells, the A value and migration number of BT-474 cells stimulated with Jolkinolide B were significantly decreased (P < 0.01, n = 6), and the number of apoptotic cells was significantly increased (P < 0.01, n = 6). Akt and p-Akt protein levels in the two breast cancer cell lines in the Jolkinolide B group were all decreased (P < 0.01, n = 6), especially in BT-474 cells stimulated by Jolkinolide B. CONCLUSION: Jolkinolide B regulates the luminal A and luminal B subtypes of breast cancer through PI3K-Akt, EGFR and other pathways. Jolkinolide B has more significant therapeutic effect on luminal B subtype breast cancer. In vitro, experiments verified that Jolkinolide B significantly inhibited the proliferation and migration activity of BT-474 breast cancer cells by downregulating the PI3K-Akt pathway.

2.
Front Cell Dev Biol ; 9: 742662, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616745

RESUMO

The involvement of cardiomyopathy during sepsis means higher mortality and prolonged length of hospital stay. Many efforts have been made to alleviate the apoptosis of cardiomyocytes in sepsis. The huge potential of IL-13 in tissue repair has attracted increasing attention. In the present study, we used LPS-treated mice or primary cardiomyocytes as a sepsis model to explore the anti-apoptotic ability of IL-13. It was found that an increased level of exogenous IL-13 was beneficial to the recovery of heart function in sepsis, and this anti-apoptotic effect of IL-13 was probably through enhancing the phosphorylation of STAT3 Ser727. In addition, we identified that the heart protective effect of IL-13 was associated with type 2 innate lymphocytes (ILC2). All these findings may provide a potential promising treatment for sepsis-induced cardiomyopathy.

3.
Trials ; 22(1): 726, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674750

RESUMO

The efficient community spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the current pandemic of coronavirus disease-2019 (COVID-19), which in severe and critical cases results in progressive pulmonary infection, complicated by respiratory failure, with a high prevalence of acute respiratory distress syndrome. Of all age groups, older adults have the greatest risk of severe COVID-19 and the associated complications. Globally, there are many reports of the rapid spread of COVID-19 among residents of skilled nursing facilities, with high associated rates of morbidity and mortality. With over 1.3 million residents in nursing home care in the USA, there is an urgent need for therapeutic strategies to prevent COVID-19 in these populations.Lilly, in collaboration with the National Institute of Allergy and Infectious Diseases, conducted the BLAZE-2 trial to evaluate the efficacy and safety of the monoclonal antibody bamlanivimab (LY3819253) in preventing SARS-CoV-2 infection and COVID-19, defined as symptomatic infection, in skilled nursing and assisted living facilities. It is a phase 3 randomized, double-blind, placebo-controlled trial, where participants were randomized to bamlanivimab (4200 mg) or placebo and then followed up for 24 weeks. Conducting a trial in the midst of a pandemic in these facilities poses several challenges, including a vulnerable elderly population, travel restrictions, supply chain interruptions, and defining the target population. The operational challenges were addressed by the innovative use of mobile research units which are customized, equipped, and staffed to support BLAZE-2 randomization and participant dosing within the skilled nursing and assisted living facilities. Herein, we describe the design of the study, the analytics behind facility selection, and an innovative operational model.

4.
Front Psychol ; 12: 728165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594281

RESUMO

The present study aimed to examine the current status and influencing mechanisms of different demographic factors associated with cognitive function in urban Chinese older adults. A total of 644 older adults from 14 communities in urban China (e.g., Shanghai, Beijing, and Wuxi) were investigated by using the Mini-Mental State Examination and the Repeatable Battery for the Assessment of Neuropsychological Status. The results indicated that the overall cognitive function of older adults in urban China was normal. We found an aging effect on cognitive level, and cognitive function declined more rapidly after age 80. Older age, unmarried status, and lower occupational cognitive requirements increased the likelihood of cognitive risk. Higher educational levels and active engagement in exercise may contribute to cognitive reserve and have a protective effect on cognitive decline in late life. Further study is needed to develop appropriate interventions to improve the mental health of older people.

5.
Appl Opt ; 60(27): 8480-8484, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34612949

RESUMO

An all-fiber mode power splitter (MPS) for mode-division multiplexing (MDM) transmission is proposed and numerically investigated. The MPS is based on the configuration of the symmetric few-mode fiber (FMF) coupler, with the operation of four modes (LP01, LP11, LP21, and LP02). By comprehensively optimizing the FMF coupling parameters, including both the coupling area distance D and the coupling length L, MPSs with various power splitting ratios from 90%:10% to 50%:50% under the condition of different single guided mode injection are obtained. Then, the MPS with a 90%:10% power splitting ratio under the simultaneous injection of LP01, LP11, LP21, and LP02 modes is reported, which can be used as the mode tap for the optical performance monitoring. Moreover, based on the proposed MPS structure, selective mode power strippers with more than 25 dB mode extinction ratio for LP01, LP11, LP21, and LP02 modes are numerically verified. The arbitrary single guided mode arising in the FMF can be selectively coupled into another FMF, together with an insertion loss of less than 1 dB. Owing to the flexible setting of the mode power splitting ratio, the proposed MPS may become a potential solution to realizing system performance monitoring and mode power routing in MDM systems.

6.
Cell Death Dis ; 12(10): 863, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556632

RESUMO

Gastric cancer (GC) is considered one of the most common gastrointestinal malignancies worldwide. Circular RNAs (circRNAs) are a new class of endogenous noncoding RNAs, which can be used as biomarkers and therapeutic targets for many tumors. However, the role and potential regulatory mechanisms of circRNAs in GC remain unclear. In this study, we demonstrated that a specific circRNA, circHAS2, was upregulated in GC tissues and cells and was positively correlated with tumor metastasis. In vitro experiments demonstrated that circHAS2 knockdown or the addition of hsa-miR-944 mimics inhibited the proliferation, migration, and invasion ability of GC cells and affected the epithelial-mesenchymal transition. In addition, hsa-miR-944 interacted with protein phosphatase, Mg2+/Mn2+-dependent 1E (PPM1E), and was found to be a target gene of circHAS2. The upregulation of PPM1E reversed the effects of circHAS2 knockout on GC cells. The circHAS2/hsa-miR-944/PPM1E axis may be involved in the progression of GC; thus, circHAS2 may be a potential biomarker and therapeutic target for GC.

7.
Cell Discov ; 7(1): 89, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34580278

RESUMO

SARS-CoV-2 outbreak has been declared by World Health Organization as a worldwide pandemic. However, there are many unknowns about the antigen-specific T-cell-mediated immune responses to SARS-CoV-2 infection. Here, we present both single-cell TCR-seq and RNA-seq to analyze the dynamics of TCR repertoire and immune metabolic functions of blood T cells collected from recently discharged COVID-19 patients. We found that while the diversity of TCR repertoire was increased in discharged patients, it returned to basal level ~1 week after becoming virus-free. The dynamics of T cell repertoire correlated with a profound shift of gene signatures from antiviral response to metabolism adaptation. We also demonstrated that the top expanded T cell clones (~10% of total T cells) display the key anti-viral features in CD8+ T cells, confirming a critical role of antigen-specific T cells in fighting against SARS-CoV-2. Our work provides a basis for further analysis of adaptive immunity in COVID-19 patients, and also has implications in developing a T-cell-based vaccine for SARS-CoV-2.

8.
Nanoscale Horiz ; 6(10): 801-808, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34569583

RESUMO

The standard density functional theory (DFT) based first-principles approach has been widely used for modeling nanoscale electronic devices. A recent experiment, however, reported surprising transport properties of thiol-terminated silane junctions that cannot be understood using the standard DFT approach, presenting a severe challenge for the current computational understanding of electron transport at the nanoscale. Using the recently proposed steady-state DFT (SS-DFT) for nonequilibrium quantum systems, we found that in silane junctions, underlying the puzzling experimental observations is a novel type of intriguing nonequilibrium effect that is beyond the framework of the standard DFT approach. Our calculations show that the standard DFT approach is a good approximation of SS-DFT when silane junctions are near equilibrium, but the aforementioned nonequilibrium effects could drive the thiol-terminated silanes far away from equilibrium even at low biases of around 0.2 V. Further analysis suggests that these nonequilibrium effects could generally exist in nanoscale devices in which there are conducting channels mainly residing at the source contact and close to the bias window. These findings significantly broaden our fundamental understanding of electron transport at the nanoscale.

9.
Gastrointest Endosc ; 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34547254

RESUMO

BACKGROUND AND AIMS: White-light endoscopy (WLE) is the most pivotal tool to detect gastric cancer in the early stage. However, the skill among endoscopists varies greatly. Here, we aim to develop a deep learning-based system named ENDOANGEL-LD (lesion detection) to assist in detecting all focal gastric lesions and predicting neoplasms by WLE. METHODS: Endoscopic images were retrospectively obtained from Renmin Hospital of Wuhan University (RHWU) for the development, validation and internal test of the system. Additional external tests were conducted in 5 other hospitals to evaluate the robustness. Stored videos from RHWU were used for assessing and comparing the performance of ENDOANGEL-LD with that of experts. Prospective consecutive patients undergoing upper endoscopy were enrolled from May 6, 2021 to Aug 2 2021 in RHWU to assess clinical practice applicability. RESULTS: Over 10 thousand patients undergoing upper endoscopy were enrolled in this study. The sensitivities were 96.9% and 95.6% for detecting gastric lesions, 92.9% and 91.7% for diagnosing neoplasm in internal and external patients, respectively. In 100 videos, ENDOANGEL-LD achieved superior sensitivity and negative predictive value for detecting gastric neoplasm than that of experts (100% vs 85.5%±3.4%, p=0.003; 100% vs 86.4%±2.8%, p=0.002). In 2010 prospective consecutive patients, ENDOANGEL-LD achieved a sensitivity of 92.8% for detecting gastric lesions with 3.04±3.04 false positives per gastroscopy, and a sensitivity of 91.8% and specificity of 92.4% for diagnosing neoplasm. CONCLUSIONS: The results show that ENDOANGEL-LD has great potential for assisting endoscopists in screening gastric lesions and suspicious neoplasms in clinical work.

10.
Lipids Health Dis ; 20(1): 115, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34563222

RESUMO

BACKGROUNDS: Cancer-associated cachexia (CAC) is a metabolic syndrome characterized by progressive depletion of adipose and muscle tissue that cannot be corrected by conventional nutritional therapy. Adipose tissue, an important form of energy storage, exhibits marked loss in the early stages of CAC, which affects quality of life and efficacy of chemotherapy. MicroRNAs (miRNAs) are a class of noncoding RNAs that widely exist in all kinds of eukaryotic cells and play regulatory roles in various biological processes. However, the role of miRNAs in adipose metabolism in CAC has rarely been reported. This study attempted to identify important miRNAs in adipose metabolism in CAC and explore their mechanism to identify a new predictive marker or therapeutic target for CAC-related adipose tissue loss (CAL). METHODS: In this study, miRNA sequencing was firstly used to identify differentially expressed miRNAs related to CAL and the reliability of the conclusions was verified in large population samples. Furthermore, functional experiments were performed by up and down regulating miR-410-3p in adipocytes. The binding of miR-410-3p to Insulin Receptor Substrate 1 (IRS-1) was verified by Luciferase reporter assay and functional experiments of IRS-1 were performed in adipocytes. Finally, the expression of miR-410-3p in serum exosomes was detected. RESULTS: miR-410-3p was selected as differentially expressed miRNA through screening and validation. Adipogenesis was suppressed in miR-410-3p upregulation experiment and increased in downregulation experiment. Luciferase reporter assay showed that miR-410-3p binds to 3' non-coding region of IRS-1 and represses its expression and ultimately inhibits adipogenesis. miR-410-3p was highly expressed in serum exosomes of CAC patients, which was consistent with results in adipose tissue. CONCLUSIONS: The expression of miR-410-3p was higher in subcutaneous adipose tissues and serum exosomes of CAC patients, which significantly inhibits adipogenesis and lipid accumulation. The study shows that miR-410-3p could downregulate IRS-1 and downstream adipose differentiation factors including C/EBP-a and PPAR-γ by targeting 3' noncoding region.

12.
Cell Rep Med ; 2(8): 100353, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34467243

RESUMO

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1+ ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC.

13.
Front Cell Dev Biol ; 9: 695007, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497805

RESUMO

A group of circulating microRNAs (miRNAs) have been implicated in the pathogenesis of Parkinson's disease. However, a comprehensive study of the interactions between pathogenic miRNAs and their downstream Parkinson's disease (PD)-related target genes has not been performed. Here, we identified the miRNA expression profiles in the plasma and circulating exosomes of Parkinson's disease patients using next-generation RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that the miRNA target genes were enriched in axon guidance, neurotrophin signaling, cellular senescence, and the Transforming growth factor-ß (TGF-ß), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) signaling pathways. Furthermore, a group of aberrantly expressed miRNAs were selected and further validated in individual patient plasma, human neural stem cells (NSCs) and a rat model of PD. More importantly, the full scope of the regulatory network between these miRNAs and their PD-related gene targets in human neural stem cells was examined, and the findings revealed a similar but still varied downstream regulatory cascade involving many known PD-associated genes. Additionally, miR-23b-3p was identified as a novel direct regulator of alpha-synuclein, which is possibly the key component in PD. Our current study, for the first time, provides a glimpse into the regulatory network of pathogenic miRNAs and their PD-related gene targets in PD. Moreover, these PD-associated miRNAs may serve as biomarkers and novel therapeutic targets for PD.

14.
Clin Nutr ; 40(9): 5156-5161, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34461589

RESUMO

BACKGROUND & AIMS: Adipose tissue loss is one of the features in patients with cancer cachexia. However, whether subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) contribute differently to the progress of cancer cachexia in gastric cancer patients with cachexia remains unclear. This study aim to investigate the effect of SAT and VAT in gastric cancer patients with cachexia. METHODS: Gastric cancer patients who underwent surgery were divided into cancer cachexia group and non-cachexia group. A new deep learning system was developed to segment SAT and VAT from the computed tomography images at the third lumbar vertebra. Indexes of SAT (SATI) and VAT (VATI) were compared between cachexia and non-cachexia groups. The prognostic values of SATI and VATI for patients with gastric cancer cachexia were analyzed by Kaplan-Meier method and Cox regression. RESULTS: A total of 1627 gastric cancer patients (411 cachexia and 1216 non-cachexia) were included in this study. A new V-Net-Based segmentation deep learning system was developed to quickly (0.02 s/image) and accurately segment SAT (dice scores = 0.96) and VAT (dice scores = 0.98). The SATI of gastric cancer patients with cachexia were significantly lower than non-cachexia patients (44.91 ± 0.90 vs. 50.92 ± 0.71 cm2/m2, P < 0.001), whereas no significant difference was detected in VATI (35.98 ± 0.84 VS. 37.90 ± 0.45 cm2/m2, P = 0.076). Cachexia patients with low SATI showed poor survival than those with high SATI (HR = 1.35; 95% CI = 1.06-1.74). In contrast, VATI did not show close correlation with survival in patients with cachexia (HR = 1.18; 95% CI = 0.92-1.51). CONCLUSION: SAT and VAT showed different effects on gastric cancer patients with cachexia. More attention should be paid to the loss of SAT during the progress of cancer cachexia.

15.
Org Lett ; 23(18): 7112-7117, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34459613

RESUMO

A photochemical protocol that couples diarylamines and α-ketoesters to afford the chiral 3-hydroxyoxindoles through tandem photoredox and chiral phosphoric acid catalysis is developed. The reaction involves an enantioselective photochemical radical-radical cross-coupling process. The chiral phosphoric acid is discovered to play crucial roles by decreasing the reductive potentials of α-ketoesters and stereocontrolling the downstream asymmetric radical-radical cross-coupling via the formation of pentacoordinate complex.

16.
Pharm Biol ; 59(1): 974-985, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34348563

RESUMO

CONTEXT: Eriodictyol (EDT) is a flavonoid with strong anti-inflammatory, anti-apoptotic, and antioxidant properties. OBJECTIVE: To investigate the protective effect and mechanism of EDT in ulcerative colitis (UC). MATERIALS AND METHODS: UC model was induced by 3% dextran sulphate sodium (DSS) solution for 7 days, meanwhile, EDT and Smoothened (Smo) inhibitor cyclopamine (Cyc) were intraperitoneally injected. In the first experiment, C57BL/6 mice divided into blank control, DSS, DSS + EDT (20 or 40 mg/kg) groups. In second experiment, added Cyc (5 mg/kg) and EDT + Cyc groups. All mice were sacrificed on day 8. Disease activity index (DAI), colon length and colon histology as well as MDA levels, SOD, and GSH-Px activities were measured. The expression of Sonic hedgehog (Shh), Patched, Smo, glioblastoma-1, zonula occludens-1 (ZO-1), occludin, cleaved caspase 3, Bax and Bcl-2 in colon was detected using RT-PCR and Western blotting. RESULTS: After EDT treatment, compared with the DSS group, DAI (2.33 ± 0.516 vs. 3.67 ± 0.516), colon shortening (5.27 ± 0.476 vs. 4.53 ± 0.528 cm) and histological score (6.67 ± 1.211 vs. 12 ± 1.265) was significantly decreased. EDT also reduced inflammation, oxidative stress and apoptosis in colon. Additionally, EDT increased the expression of the tight junction proteins ZO-1 (35%) and occludin (66.3%). Mechanistically, EDT upregulated the Shh signalling pathway. However, Cyc-mediated inhibition of the Shh pathway partially abolished the effects of EDT. DISCUSSION AND CONCLUSIONS: These results indicate EDT attenuates DSS-induced colitis by activating the Shh pathway. Further clinical trials are needed to demonstrate its efficacy on UC.

17.
Front Immunol ; 12: 708678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381457

RESUMO

Innate lymphoid cells (ILCs) are emerging as important players in inflammatory diseases. The oral mucosal barrier harbors all ILC subsets, but how these cells regulate the immune responses in periodontal ligament tissue during periodontitis remains undefined. Here, we show that total ILCs are markedly increased in periodontal ligament of periodontitis patients compared with healthy controls. Among them, ILC1s and ILC3s, particularly NKp44+ILC3 subset, are the predominant subsets accumulated in the periodontal ligament. Remarkably, ILC1s and ILC3s from periodontitis patients produce more IL-17A and IFN-γ than that from healthy controls. Collectively, our results highlight the role of ILCs in regulating oral immunity and periodontal ligament inflammation and provide insights into targeting ILCs for the treatment of periodontitis.

18.
Plant Cell Physiol ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34463342

RESUMO

AP2 subfamily transcription factors participate in plant growth and development, but their roles in plant immunity remain unclear. Here, we discovered that the AP2 transcription factor CaAIL1 functions in immunity against Ralstonia solanacearum infection (RSI) in pepper (Capsicum annuum). CaAIL1 expression was upregulated by RSI, and loss- and gain-of-function assays using virus-induced gene silencing and transient overexpression, respectively, revealed that CaAIL1 plays a positive role in immunity to RSI in pepper. Chromatin immunoprecipitation sequencing (ChIP-seq) uncovered a subset of transcription-factor-encoding genes, including CaRAP2-7, CaGATA17, CaGtf3a and CaTCF25, that were directly targeted by CaAIL1 via their cis-elements, such as GT or AGGCA motifs. ChIP-qPCR and electrophoretic mobility shift assays confirmed these findings. These genes, encoding transcription factors with negative roles in immunity, were repressed by CaAIL1 during pepper response to RSI, whereas genes encoding positive immune regulators such as CaEAS were derepressed by CaAIL1. Importantly, we showed that the atypical EAR motif (LXXLXXLXX) in CaAIL1 is indispensable for its function in immunity. These findings indicate that CaAIL1 enhances the immunity of pepper against RSI by repressing a subset of negative immune regulators during the RSI response through its binding to several cis-elements in their promoters.

19.
Cancer Cell ; 39(10): 1308-1310, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34450049

RESUMO

The precise role of intestinal ILC3s in cancer remains largely unknown. Published in Cell, Goc et al. describe ILC3 function and plasticity in tumors. ILC3s may lose their identity and thus become either ILC1s or exhausting-ILC3s, which could in turn reshape the gut microbiome for colorectal cancer progression and immunotherapy resistance.

20.
Mucosal Immunol ; 14(6): 1306-1322, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34349237

RESUMO

Group 2 innate lymphoid cells (ILC2s) manifest tissue heterogeneity and are crucial modulators of regional immune responses. The molecular mechanisms regulating tissue ILC2 properties remain elusive. Here, we interrogate the signatures of ILC2s from five tissues at the transcriptome and epigenetic level. We have found that tissue microenvironment strongly shapes ILC2 identities. The intestine induces Aiolos+ILC2s, whereas lung and pancreas enhance Galectin-1+ILC2s. Though being a faithful gut ILC2 feature under the steady state, Aiolos is induced in non-intestinal ILC2s by pro-inflammatory cytokines. Specifically, IL-33 stimulates Aiolos expression in both human and mouse non-intestinal ILC2s. Functionally, Aiolos facilitates eosinophil recruitment by supporting IL-5 production and proliferation of ST2+ILC2s through inhibiting PD-1. At the epigenetic level, ILC2 tissue characters are imprinted by open chromatin regions (OCRs) at non-promoters. Intestinal-specific transcription factor aryl hydrocarbon receptor (Ahr) binds to Ikzf3 (encoding Aiolos) locus, increases the accessibility of an intestinal ILC2-specific OCR, and promotes the Ikzf3 transcription by enhancing H3K27ac. Consequently, Ahr prevents ILC2s entering an "exhausted-like" state through sustaining Aiolos expression. Our work elucidates mechanism of ILC2 tissue adaptation and highlights Aiolos as a potential target of type 2 inflammation.

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