Browsing by Author "Liu, Hong"
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Item AMP kinase promotes Bcl6 expression in both mouse and human T cells(Elsevier, 2017-01) Xie, Markus M.; Amet, Tohti; Liu, Hong; Yu, Qigui; Dent, Alexander L.; Department of Microbiology and Immunology, School of MedicineThe transcription factor Bcl6 is a master regulator of follicular helper T (TFH) cells, and understanding the signaling pathway that induces Bcl6 and TFH cell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how TFH cells evade IL-2 inhibition is not completely understood. Here we show that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation (GD), and this pathway is insensitive to inhibition by IL-2. Similar to GD, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, and 2DG induced Bcl6 expression in activated CD4 T cells. The metabolic sensor AMP kinase (AMPK) is activated when glycolysis is decreased, and the induction of Bcl6 by GD was inhibited by the AMPK antagonist compound C. Additionally, activation of AMPK by the drug AICAR caused Bcl6 up-regulation in activated CD4 T cells. When mice were immunized with KLH using AICAR as an adjuvant, there was a strong TFH–dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in TFH cells in vivo. Activation of AMPK strongly induced BCL6 and the up-regulation of TFH cell marker expression by human CD4 T cells. Our data reveal a major new pathway for TFH cell differentiation, conserved by both mouse and human T cells. Mature TFH cells are reported to have a lower metabolic state compared to TH1 cells. Our data indicates that decreased metabolism may be deterministic for TFH cell differentiation, and not simply a result of TFH cell differentiation.Item Characterization of intratumor microbiome in cancer immunotherapy(Elsevier, 2023-07-12) Zhang, Zhao; Gao, Qian; Ren, Xiangmei; Luo, Mei; Liu, Yuan; Liu, Peilin; Liu, Yun; Ye, Youqiong; Che, Xiang; Liu, Hong; Han, Leng; Biostatistics and Health Data Science, School of MedicineItem Development of allergen-specific IgE in a food-allergy model requires precisely timed B cell stimulation and is inhibited by Fgl2(Cell Press, 2022) Chen, Qiang; Xie, Markus; Liu, Hong; Dent, Alexander L.; Microbiology and Immunology, School of MedicineImmunoglobulin E (IgE) responses are a central feature of allergic disease. Using a well-established food-allergy model in mice, we show that two sensitizations with cognate B cell antigen (Ag) and adjuvant 7 days apart promotes optimal development of IgE+ germinal center (GC) B cells and high-affinity IgE production. Intervals of 3 or 14 days between Ag sensitizations lead to loss of IgE+ GC B cells and an undetectable IgE response. The immunosuppressive factors Fgl2 and CD39 are down-regulated in T follicular helper (TFH) cells under optimal IgE-sensitization conditions. Deletion of Fgl2 in TFH and T follicular regulatory (TFR) cells, but not from TFR cells alone, increase Ag-specific IgE levels and IgE-mediated anaphylactic responses. Overall, we find that Ag-specific IgE responses require precisely timed stimulation of IgE+ GC B cells by Ag. Furthermore, we show that Fgl2 is expressed by TFH cells and represses IgE. This work has implications for the development and treatment of food allergies.Item Effect of Esketamine Added to Propofol Sedation on Desaturation and Hypotension in Bidirectional Endoscopy: A Randomized Clinical Trial(American Medical Association, 2023-12-01) Song, Nan; Yang, Yi; Zheng, Zhong; Shi, Wen-Cheng; Tan, Ai-Ping; Shan, Xi-Sheng; Liu, Hong; Meng, Lingzhong; Peng, Ke; Ji, Fu-Hai; Anesthesia, School of MedicineImportance: Propofol sedation is widely used for endoscopic procedures, but it poses risks of hemodynamic and respiratory depression. The addition of esketamine as an adjuvant may reduce propofol requirements and associated adverse events. Objective: To evaluate the effects of low-dose esketamine added to propofol-based sedation on desaturation and hypotension during same-visit bidirectional endoscopy. Design, setting, and participants: This multicenter, double-blind, placebo-controlled randomized clinical trial assessed patients from 3 teaching hospitals in China who were scheduled for same-visit bidirectional endoscopy between February 8 and November 30, 2022, and randomly assigned to receive esketamine or normal saline (placebo). Interventions: After induction of sedation with 0.1 μg/kg of sufentanil and 0.5 mg/kg of propofol, patients in the esketamine group received 0.15 mg/kg of intravenous esketamine, whereas patients in the placebo group received an equivalent volume of saline. Sedation was achieved through propofol titration. Main outcomes and measures: The primary outcome was the composite of desaturation and hypotension during the procedures. Secondary outcomes included desaturation, hypotension, propofol requirements, postprocedure pain and fatigue, nausea or vomiting, dizziness or headache, hallucination or nightmare, endoscopist satisfaction, and patient satisfaction. Results: Among the 663 initially enrolled patients, 660 completed the study (median [IQR] age, 48 [36-57] years; 355 [53.8%] female), with 331 randomized to the esketamine group and 329 to the placebo group. The administration of esketamine compared with placebo significantly reduced the incidence of the composite outcome of desaturation and hypotension (8.2% vs 21.0%; difference, -12.8 percentage points; odds ratio [OR], 0.34; 95% CI, 0.21-0.54; P < .001). Additionally, esketamine led to significantly lower incidences of desaturation (OR, 0.36; 95% CI, 0.18-0.72; false discovery rate q = .01) and hypotension (OR, 0.33; 95% CI, 0.18-0.60; q < .001) and reduced propofol requirements (difference, -58.9 mg; 95% CI, -65.7 to -52.2 mg; q < .001), without significant effects on other secondary outcomes. Conclusions and relevance: In this randomized clinical trial of patients undergoing same-visit bidirectional endoscopy, the administration of low-dose esketamine resulted in an approximately 61% reduction in the incidence of desaturation and hypotension, accompanied by decreased propofol requirements. These findings support the use of esketamine as an adjuvant to propofol-based sedation in endoscopic procedures.Item Evidence that High Affinity IgE Can Develop in the Germinal Center in the Absence of an IgG1-switched Intermediate(American Association of Immunologists, 2023) Chen, Qiang; Liu, Hong; Luling, Noelle; Reinke, Julia; Dent, Alexander L.; Microbiology and Immunology, School of MedicineHigh affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High affinity antibodies (Abs) are formed by successive rounds of selection of Ag-specific B cells in the germinal center (GC), however several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the “indirect switching pathway” for IgE, has been described whereby Ag-specific B cells initially switch to the IgG1 isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high affinity IgE develops in the GC but we did not test the indirect switching model. Here we analyzed the importance of the indirect switching pathway by constructing IgG1-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgG1, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgG1-cre Bcl6-fl/fl mice with our food allergy model, we found that as expected, IgG1 Abs had decreased affinity, but unexpectedly the affinity of IgE for allergen was unchanged. IgG1-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high affinity IgE. Thus, in a food allergy response, high affinity IgE can be efficiently formed in the absence of indirect switching to IgG1, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE.Item Follicular regulatory T cells inhibit the development of granzyme B-expressing follicular helper T cells(American Society for Clinical Investigation, 2019-08-22) Xie, Markus M.; Fang, Shuyi; Chen, Qiang; Liu, Hong; Wan, Jun; Dent, Alexander L.; Microbiology and Immunology, School of MedicineT follicular regulatory (TFR) cells are found in the germinal center (GC) response and help shape the antibody (Ab) response. However, the precise role of TFR cells in the GC is controversial. Here, we addressed TFR cell function using mice with impaired TFR cell development (Bcl6-flox/Foxp3-cre, or Bcl6FC mice), mice with augmented TFR cell development (Blimp1-flox/Foxp3-cre, or Blimp1FC mice), and two different methods of immunization. Unexpectedly, GC B cell levels positively correlated with TFR cell levels. Using a gene profiling approach, we found that TFH cells from TFR-deficient mice showed strong upregulation of granzyme B (Gzmb) and other effector CD8+ T cell genes, many of which were Stat4 dependent. The upregulation of cytotoxic genes was the highest in TFH cells from TFR-deficient mice where Blimp1 was also deleted in Foxp3+ regulatory T cells (Bcl6-flox/Prdm1-flox/Foxp3-cre [DKO] mice). Granzyme B- and Eomesodermin-expressing TFH cells correlated with a higher rate of apoptotic GC B cells. Klrg1+ TFH cells from DKO mice expressed higher levels of Gzmb. Our data show that TFR cells repress the development of abnormal cytotoxic TFH cells, and the presence of cytotoxic TFH cells correlates with a lower GC and Ab response. Our data show what we believe is a novel mechanism of action for TFR cells helping the GC response.Item Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice(Wiley, 2016-05) Wu, Hao; Chen, Yuxin; Liu, Hong; Xu, Lin-Lin; Teuscher, Paula; Wang, Shixia; Lu, Shan; Dent, Alexander L.; Department of Microbiology & Immunology, IU School of MedicineFollicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) cells, modulate this process. However, Tfr-cell function in the GC is not well understood. Here, we define Tfr cells as a CD4(+) Foxp3(+) CXCR5(hi) PD-1(hi) CD25(low) TIGIT(high) T-cell population. Furthermore, we have used a novel mouse model ("Bcl6FC") to delete the Bcl6 gene in Foxp3(+) T cells and thus specifically deplete Tfr cells. Following immunization, Bcl6FC mice develop normal Tfh- and GCB-cell populations. However, Bcl6FC mice produce altered antigen-specific antibody responses, with reduced titers of IgG and significantly increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV-1 gp120 "prime-boost" vaccine model. In an autoimmune lupus model, we observed strongly elevated anti-DNA IgA titers in Bcl6FC mice. Additionally, Tfh cells from Bcl6FC mice consistently produce higher levels of Interferon-γ, IL-10 and IL-21. Loss of Tfr cells therefore leads to highly abnormal Tfh-cell and GCB-cell responses. Overall, our study has uncovered unique regulatory roles for Tfr cells in the GC response.Item An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T cells(American Association of Immunologists, 2015-09) Wu, Hao; Xu, Lin-lin; Teuscher, Paulla; Liu, Hong; Kaplan, Mark H.; Dent, Alexander L.; Department of Microbiology and Immunology, IU School of MedicineThe transcription factor Bcl6 is required for the development of the follicular helper T (TFH) cells. Cytokines that activate Stat3 promote Bcl6 expression and TFH cell differentiation. Previous studies with an acute virus infection model showed that TFH cell differentiation was decreased but not blocked in the absence of Stat3. In this study, we further analyzed the role of Stat3 in TFH cells. In Peyer’s patches (PPs), we found that compared to wild-type, Stat3-deficient TFH cells developed at a 25% lower rate, and expressed increased IFNγ and IL-4. While PP germinal center B (GCB) cells developed at normal numbers with Stat3-deficient TFH cells, IgG1 class switching was greatly increased. Following immunization with Sheep Red Blood Cells (SRBC), splenic Stat3-deficient TFH cells developed at a slower rate than in control mice and splenic GCB cells were markedly decreased. Stat3-deficient TFH cells developed poorly in a competitive bone marrow chimera environment. Under all conditions tested, Stat3-deficient TFH cells over-expressed both IL-4 and Bcl6, a pattern specific for the TFH cell population. Finally, we found in vitro that repression of IL-4 expression in CD4 T cells by Bcl6 required Stat3 function. Our data indicate that Stat3 can repress the expression of Bcl6 and IL-4 in TFH cells, and that Stat3 regulates the ability of Bcl6 to repress target genes. Overall, we conclude that Stat3 is required to fine-tune the expression of multiple key genes in TFH cells, and that the specific immune environment determines the function of Stat3 in TFH cells.Item Mechanical loading attenuates breast cancer-associated bone metastasis in obese mice by regulating the bone marrow microenvironment(Wiley, 2021) Huang, Menglu; Liu, Hong; Zhu, Lei; Li, Xinle; Li, Jie; Yang, Shuang; Liu, Daquan; Song, Xiaomeng; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, School of Engineering and TechnologyBreast cancer, a common malignancy for women, preferentially metastasizes to bone and obesity elevates the chance of its progression. While mechanical loading can suppress obesity and tumor-driven osteolysis, its effect on bone-metastasized obese mice has not been investigated. Here, we hypothesized that mechanical loading can lessen obesity-associated bone degradation in tumor-invaded bone by regulating the fate of bone marrow-derived cells. In this study, the effects of mechanical loading in obese mice were evaluated through X-ray imaging, histology, cytology, and molecular analyses. Tumor inoculation to the tibia elevated body fat composition, osteolytic lesions, and tibia destruction, and these pathologic changes were stimulated by the high-fat diet (HFD). However, mechanical loading markedly reduced these changes. It suppressed osteoclastogenesis by downregulating receptor activator of nuclear factor Kappa-B ligand and cathepsin K and promoted osteogenesis, which was associated with the upregulation of OPG and downregulation of C/enhancer-binding protein alpha and proliferator-activated receptor gamma for adipogenic differentiation. Furthermore, it decreased the levels of tumorigenic genes such as Rac1, MMP9, and interleukin 1β. In summary, this study demonstrates that although a HFD aggravates bone metastases associated with breast cancer, mechanical loading significantly protected tumor-invaded bone by regulating the fate of bone marrow-derived cells. The current study suggests that mechanical loading can provide a noninvasive, palliative option for alleviating breast cancer-associated bone metastasis, in particular for obese patients.Item PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury(Taylor & Francis, 2018) Tang, Chengyuan; Han, Hailong; Yan, Mingjuan; Zhu, Shiyao; Liu, Jing; Liu, Zhiwen; He, Liyu; Tan, Jieqiong; Liu, Yu; Liu, Hong; Sun, Lin; Duan, Shaobin; Peng, Youming; Liu, Fuyou; Yin, Xiao-Ming; Zhang, Zhuohua; Dong, Zheng; Pathology and Laboratory Medicine, School of MedicineDamaged or dysfunctional mitochondria are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Therefore, timely removal of these organelles is critical to cellular homeostasis and viability. Mitophagy is the mechanism of selective degradation of mitochondria via autophagy. The significance of mitophagy in kidney diseases, including ischemic acute kidney injury (AKI), has yet to be established, and the involved pathway of mitophagy remains poorly understood. Here, we show that mitophagy is induced in renal proximal tubular cells in both in vitro and in vivo models of ischemic AKI. Mitophagy under these conditions is abrogated by Pink1 and Park2 deficiency, supporting a critical role of the PINK1-PARK2 pathway in tubular cell mitophagy. Moreover, ischemic AKI is aggravated in pink1 andpark2 single- as well as double-knockout mice. Mechanistically, Pink1 and Park2 deficiency enhances mitochondrial damage, reactive oxygen species production, and inflammatory response. Taken together, these results indicate that PINK1-PARK2-mediated mitophagy plays an important role in mitochondrial quality control, tubular cell survival, and renal function during AKI.