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1
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Oyende Y, Taus LJ, Fatatis A. IL-1β in Neoplastic Disease and the Role of Its Tumor-Derived Form in the Progression and Treatment of Metastatic Prostate Cancer. Cancers (Basel) 2025; 17:290. [PMID: 39858071 PMCID: PMC11763358 DOI: 10.3390/cancers17020290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Since its discovery, IL-1β has taken center stage as a key mediator of a very broad spectrum of diseases revolving around immuno-mediated and inflammatory events. Predictably, the pleiotropic nature of this cytokine in human pathology has led to the development of targeted therapeutics with multiple treatment indications in the clinic. Following the accumulated findings of IL-1β's central modulatory role in the immune system and the implication of inflammatory pathways in cancer, the use of IL-1β antagonists was first proposed and then also pursued for oncology disorders. However, this approach has consistently relied on the perceived need of interfering with IL-1β synthesized and secreted by immune cells. Herein, we discuss the importance of IL-1β derived from cancer cells which impacts primary tumors, particularly metastatic lesions, separately from and in addition to its more recognized role in immune-mediated inflammatory events. To this end, we focus on the instrumental contribution of IL-1β in the establishment and progression of advanced prostate adenocarcinoma. Special emphasis is placed on the potential role that the standard-of-care treatment strategies for prostate cancer patients have in unleashing IL-1β expression and production at metastatic sites. We conclude by reviewing the therapeutics currently used for blocking IL-1β signaling and propose a rationale for their concomitant use with standard-of-care treatments to improve the clinical outcomes of advanced prostate cancer.
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Affiliation(s)
- Yetunde Oyende
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Y.O.); (L.J.T.)
| | - Luke J. Taus
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Y.O.); (L.J.T.)
| | - Alessandro Fatatis
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Y.O.); (L.J.T.)
- Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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2
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Zhang X, Jin T, Wang H, Han S, Liang Y. Microglia in morphine tolerance: cellular and molecular mechanisms and therapeutic potential. Front Pharmacol 2024; 15:1499799. [PMID: 39669194 PMCID: PMC11635611 DOI: 10.3389/fphar.2024.1499799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 11/15/2024] [Indexed: 12/14/2024] Open
Abstract
Morphine has a crucial role in treating both moderate to severe pain and chronic pain. However, prolonged administration of morphine can lead to tolerance of analgesia, resulting in increased doses and poor treatment of pain. Many patients, such as those with terminal cancer, require high doses of morphine for long periods. Addressing morphine tolerance can help this group of patients to escape pain, and the mechanisms behind this need to be investigated. Microglia are the key cells involved in morphine tolerance and chronic morphine administration leads to microglia activation, which in turn leads to activation of internal microglia signalling pathways and protein transcription, ultimately leading to the release of inflammatory factors. Inhibiting the activation of microglia internal signalling pathways can reduce morphine tolerance. However, the exact mechanism of how morphine acts on microglia and ultimately leads to tolerance is unknown. This article discusses the mechanisms of morphine induced microglia activation, reviews the signalling pathways within microglia and the associated therapeutic targets and possible drugs, and provides possible directions for clinical prevention or retardation of morphine induced analgesic tolerance.
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Affiliation(s)
- Xiangning Zhang
- Department of Anesthesiology, Women and Children’s Hospital, Peking University People’s Hospital, Qingdao University, Qingdao, Shandong, China
- Clinical Medical College, Qingdao University, Qingdao, Shandong, China
| | - Tingting Jin
- Department of Anesthesiology, Women and Children’s Hospital, Peking University People’s Hospital, Qingdao University, Qingdao, Shandong, China
- Clinical Medical College, Qingdao University, Qingdao, Shandong, China
| | - Haixia Wang
- Department of Anesthesiology, Women and Children’s Hospital, Peking University People’s Hospital, Qingdao University, Qingdao, Shandong, China
- Clinical Medical College, Qingdao University, Qingdao, Shandong, China
| | - Shuai Han
- Department of Anesthesiology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yongxin Liang
- Department of Anesthesiology, Women and Children’s Hospital, Peking University People’s Hospital, Qingdao University, Qingdao, Shandong, China
- Clinical Medical College, Qingdao University, Qingdao, Shandong, China
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3
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Chemello C, Facci L, Marcolin E, Ramaschi GE, Barbierato M, Giusti P, Bolego C, Zusso M. Fentanyl enhances immune cell response through TLR4/MD-2 complex. Front Pharmacol 2024; 15:1468644. [PMID: 39444612 PMCID: PMC11496304 DOI: 10.3389/fphar.2024.1468644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/27/2024] [Indexed: 10/25/2024] Open
Abstract
Introduction Opioids have been shown to induce neuroinflammation and immune cell activation, that might contribute to some of the opioid side effects, such as opioid-induced tolerance and paradoxical hyperalgesia. In this context, TLR4/MD-2 complex has been proposed as an off-target site for opioid action. This study was aimed at investigating the effect of fentanyl on lipopolysaccharide (LPS)-induced TLR4/MD-2 activation in rat primary microglia and human monocyte-derived macrophages (MDM). Materials and Methods The effect of fentanyl was first explored by measuring the expression and release of different proinflammatory mediators in primary rat microglia and human MDM by real-time PCR and ELISA. Then, the involvement of TLR4/MD-2 signaling was investigated studying NF-κB activation in HEK293 cells stably transfected with human TLR4, MD-2, and CD14 genes (HEK-Blue hTLR4 cells) and in human MDM. Results Fentanyl increased mRNA levels, as well as the LPS-induced secretion of proinflammatory mediators in primary microglia and MDM. Two inhibitors of TLR4/MD-2 signaling, namely the oxazoline derivative of N-palmitoylethanolamine (PEA-OXA) and CLI-095, blocked the production and release of proinflammatory cytokines by microglia stimulated with LPS and fentanyl, suggesting that TLR4/MD-2 could be the target of the proinflammatory activity of fentanyl. Finally, we showed that fentanyl in combination with LPS activated NF-κB signaling in human MDM and in HEK-Blue hTLR4 cells and this effect was blocked by inhibitors of TLR4/MD-2 complex. Discussion These results provide new insight into the mechanism of the proinflammatory activity of fentanyl, which involves the activation of TLR4/MD-2 signaling. Our findings might facilitate the development of novel inhibitors of TLR4/MD-2 signaling to combine with opioid-based analgesics for effective and safe pain management.
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Affiliation(s)
| | | | | | | | | | | | | | - Morena Zusso
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
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Luo Y, Su B, Hung V, Luo Y, Shi Y, Wang G, de Graaf D, Dinarello CA, Spaner DE. IL-1 receptor antagonism reveals a yin-yang relationship between NFκB and interferon signaling in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2024; 121:e2405644121. [PMID: 39121163 PMCID: PMC11331101 DOI: 10.1073/pnas.2405644121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/10/2024] [Indexed: 08/11/2024] Open
Abstract
Nuclear factor kappa B (NFκB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NFκB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NFκB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NFκB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NFκB and oxidative stress in the leukemia cells. However, inhibition of NFκB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells in vitro that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time.
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Affiliation(s)
- YuXuan Luo
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
- Department of Immunology, University of Toronto, TorontoM5S 1A8, Canada
| | - BoYang Su
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
- Department of Medical Biophysics, University of Toronto, TorontoM5G 2M9, Canada
| | - Vincent Hung
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
| | - YuHan Luo
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
- Department of Immunology, University of Toronto, TorontoM5S 1A8, Canada
| | - Yonghong Shi
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
| | - Guizhi Wang
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
| | - Dennis de Graaf
- Department of Medicine, University of Colorado Denver, Denver, CO80045
- Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn53127, Germany
| | - Charles A. Dinarello
- Department of Medicine, University of Colorado Denver, Denver, CO80045
- Department of Medicine, Radboud University Medical Center, Nijmegen6525 GA, The Netherlands
| | - David E. Spaner
- Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, TorontoM4N 3M5, Canada
- Department of Immunology, University of Toronto, TorontoM5S 1A8, Canada
- Department of Medical Biophysics, University of Toronto, TorontoM5G 2M9, Canada
- Department of Hematology, Odette Cancer Center, TorontoM4N 3M5, Canada
- Department of Medicine, University of Toronto, TorontoM5G 2C4, Canada
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Shao C, Cao Y, Wang Z, Wang X, Li C, Hao X, Wang L, Du Z, Yang F, Jiang C, Wang H, Hao Y, Han J, Hou X. Soluble ST2 predicts continuous renal replacement therapy in patients receiving venoarterial extracorporeal membrane oxygenation. Perfusion 2024; 39:927-934. [PMID: 37051884 DOI: 10.1177/02676591231169410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
OBJECTIVE This study aimed to evaluate the relationship between plasma soluble ST2 (sST2) levels 24 h after extracorporeal membrane oxygenation (ECMO) initiation and continuous renal replacement therapy (CRRT) in patients receiving venoarterial ECMO (V-A ECMO) support. METHODS AND RESULTS Data of patients who received ECMO support for postcardiotomy cardiogenic shock between January 2017 and July 2019 were retrospectively collected from Beijing Anzhen Hospital, Capital Medical University. Ultimately, 116 patients were included in the present study for analysis. The concentration of sST2 was determined by enzyme-linked immunosorbent assay (ELISA). The log10 sST2 levels were higher in patients undergoing CRRT than those who did not (6.06 vs. 6.22, p = 0.019). Patients undergoing CRRT had a lower survival rate than those who did not (32.8% vs. 67.3%, p < 0.001). In the univariate logistic regression analysis, sST2, HCO3-, lactate, and creatinine levels 24 h after ECMO initiation were related to CRRT (p < 0.05). In the multivariate logistic regression analysis, HCO3- and sST2 were identified as independent risk factors for CRRT use in patients undergoing ECMO (p < 0.05). The area under receiver operator characteristic curve (AUC) for sST2 and HCO3- together was 0.72 (95% confidence interval (CI), 0.79-0.91), which was better than those of sST2 or HCO3- alone (0.63 vs. 0.67). CONCLUSIONS sST2 and HCO3-levels at 24 h after ECMO initiation were associated with CRRT and could predict CRRT use in postcardiotomy cardiogenic shock patients undergoing ECMO.
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Affiliation(s)
- Chengcheng Shao
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Yu Cao
- Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Sohu Inc, Beijing, China
| | - Zengtao Wang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Infectious Diseases, Beijing, China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaomeng Wang
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Chenglong Li
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Xing Hao
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Liangshan Wang
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Zhongtao Du
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Feng Yang
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Chunjing Jiang
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Hong Wang
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
| | - Yu Hao
- Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Sohu Inc, Beijing, China
| | - Junyan Han
- Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Sohu Inc, Beijing, China
| | - Xiaotong Hou
- Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, No.10 Tieyi Road, Beijing 100038, China
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Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, Zeng C, Zhou T, Zhang J. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9:53. [PMID: 38433280 PMCID: PMC10910037 DOI: 10.1038/s41392-024-01757-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 03/05/2024] Open
Abstract
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
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Affiliation(s)
- Qing Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizi Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, PR China
| | - Xiaomin Ye
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Xin Shen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Zeng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Zhou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Tan W, Zhang J, Dai F, Yang D, Gu R, Tang L, Liu H, Cheng YX. Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets. Mol Cell Biochem 2024; 479:467-486. [PMID: 37097332 DOI: 10.1007/s11010-023-04736-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/07/2023] [Indexed: 04/26/2023]
Abstract
The nuclear factor κappa B (NF-κB) signaling plays a well-known function in inflammation and regulates a wide variety of biological processes. Low-grade chronic inflammation is gradually considered to be closely related to the pathogenesis of Polycystic ovary syndrome (PCOS). In this review, we provide an overview on the involvement of NF-κB in the progression of PCOS particularly, such as hyperandrogenemia, insulin resistance, cardiovascular diseases, and endometrial dysfunction. From a clinical perspective, progressive recognition of NF-κB pathway provides opportunities for therapeutic interventions aimed at inhibiting pathway-specific mechanisms. With the accumulation of basic experimental and clinical data, NF-κB signaling pathway was recognized as a therapeutic target. Although there have been no specific small molecule NF-κB inhibitors in PCOS, a plethora of natural and synthetic compound have emerged for the pharmacologic intervention of the pathway. The traditional herbs developed for NF-κB pathway have become increasingly popular in recent years. Abundant evidence elucidated that NF-κB inhibitors can significantly improve the symptoms of PCOS. Herein, we summarized evidence relating to how NF-κB pathway is involved in the development and progression of PCOS. Furthermore, we present an in-depth overview of NF-κB inhibitors for therapy interventions of PCOS. Taken together, the NF-κB signaling may be a futuristic treatment strategy for PCOS.
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Affiliation(s)
- Wei Tan
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Jie Zhang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Fangfang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Dongyong Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Ran Gu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Lujia Tang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Hua Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
| | - Yan-Xiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
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Wang Y, Lou P, Xie Y, Liu S, Li L, Wang C, Du D, Chen Y, Lu Y, Cheng J, Liu J. Nutrient availability regulates the secretion and function of immune cell-derived extracellular vesicles through metabolic rewiring. SCIENCE ADVANCES 2024; 10:eadj1290. [PMID: 38354238 PMCID: PMC10866539 DOI: 10.1126/sciadv.adj1290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024]
Abstract
Extracellular vesicle (EV)-based immunotherapeutics have emerged as promising strategy for treating diseases, and thus, a better understanding of the factors that regulate EV secretion and function can provide insights into developing advanced therapies. Here, we report that nutrient availability, even changes in individual nutrient components, may affect EV biogenesis and composition of immune cells [e.g., macrophages (Mφs)]. As a proof of concept, EVs from M1-Mφ under glutamine-depleted conditions (EVGLN-) had higher yields, functional compositions, and immunostimulatory potential than EVs from conventional GLN-present medium (EVGLN+). Mechanistically, the systemic metabolic rewiring (e.g., altered energy and redox metabolism) induced by GLN depletion resulted in up-regulated pathways related to EV biogenesis/cargo sorting (e.g., ESCRT) and immunostimulatory molecule production (e.g., NF-κB and STAT) in Mφs. This study highlights the importance of nutrient status in EV secretion and function, and optimizing metabolic states and/or integrating them with other engineering methods may advance the development of EV therapeutics.
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Affiliation(s)
- Yizhuo Wang
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Peng Lou
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yijing Xie
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shuyun Liu
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lan Li
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Chengshi Wang
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Dan Du
- Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Younan Chen
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yanrong Lu
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jingqiu Cheng
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jingping Liu
- Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China
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Kookli K, Soleimani KT, Amr EF, Ehymayed HM, Zabibah RS, Daminova SB, Saadh MJ, Alsaikhan F, Adil M, Ali MS, Mohtashami S, Akhavan-Sigari R. Role of microRNA-146a in cancer development by regulating apoptosis. Pathol Res Pract 2024; 254:155050. [PMID: 38199132 DOI: 10.1016/j.prp.2023.155050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 01/12/2024]
Abstract
Despite great advances in diagnostic and treatment options for cancer, like chemotherapy surgery, and radiation therapy it continues to remain a major global health concern. Further research is necessary to find new biomarkers and possible treatment methods for cancer. MicroRNAs (miRNAs), tiny non-coding RNAs found naturally in the body, can influence the activity of several target genes. These genes are often disturbed in diseases like cancer, which perturbs functions like differentiation, cell division, cell cycle, apoptosis and proliferation. MiR-146a is a commonly and widely used miRNA that is often overexpressed in malignant tumors. The expression of miR-146a has been correlated with many pathological and physiological changes in cancer cells, such as the regulation of various cell death paths. It's been established that the control of cell death pathways has a huge influence on cancer progression. To improve our understanding of the interrelationship between miRNAs and cancer cell apoptosis, it's necessary to explore the impact of miRNAs through the alteration in their expression levels. Research has demonstrated that the appearance and spread of cancer can be mitigated by moderating the expression of certain miRNA - a commencement of treatment that presents a hopeful approach in managing cancer. Consequently, it is essential to explore the implications of miR-146a with respect to inducing different forms of tumor cell death, and evaluate its potential to serve as a target for improved chemotherapy outcomes. Through this review, we provide an outline of miR-146a's biogenesis and function, as well as its significant involvement in apoptosis. As well, we investigate the effects of exosomal miR-146a on the promotion of apoptosis in cancer cells and look into how it could possibly help combat chemotherapeutic resistance.
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Affiliation(s)
- Keihan Kookli
- International Campus, Iran University of Medical Sciences, Tehran, Iran
| | | | - Eman Fathy Amr
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Shakhnoza B Daminova
- Department of Prevention of Dental Diseases, Tashkent State Dental Institute, Tashkent, Uzbekistan; Department of Scientific affairs, Tashkent Medical Pediatric Institute, Bogishamol Street 223, Tashkent, Uzbekistan
| | - Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia; School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | | | | | - Saghar Mohtashami
- University of California Los Angeles, School of Dentistry, Los Angeles, CA, USA.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland
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10
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Immormino RM, Smeekens JM, Mathai PI, Clough KM, Nguyen JT, Ghio AJ, Cook DN, Kulis MD, Moran TP. Different airborne particulates trigger distinct immune pathways leading to peanut allergy in a mouse model. Allergy 2024; 79:432-444. [PMID: 37804001 PMCID: PMC11017991 DOI: 10.1111/all.15908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/21/2023] [Accepted: 09/13/2023] [Indexed: 10/08/2023]
Abstract
BACKGROUND Environmental exposure to peanut through non-oral routes is a risk factor for peanut allergy. Early-life exposure to air pollutants, including particulate matter (PM), is associated with sensitization to foods through unknown mechanisms. We investigated whether PM promotes sensitization to environmental peanut and the development of peanut allergy in a mouse model. METHODS C57BL/6J mice were co-exposed to peanut and either urban particulate matter (UPM) or diesel exhaust particles (DEP) via the airways and assessed for peanut sensitization and development of anaphylaxis following peanut challenge. Peanut-specific CD4+ T helper (Th) cell responses were characterized by flow cytometry and Th cytokine production. Mice lacking select innate immune signaling genes were used to study mechanisms of PM-induced peanut allergy. RESULTS Airway co-exposure to peanut and either UPM- or DEP-induced systemic sensitization to peanut and anaphylaxis following peanut challenge. Exposure to UPM or DEP triggered activation and migration of lung dendritic cells to draining lymph nodes and induction of peanut-specific CD4+ Th cells. UPM- and DEP-induced distinct Th responses, but both stimulated expansion of T follicular helper (Tfh) cells essential for peanut allergy development. MyD88 signaling was critical for UPM- and DEP-induced peanut allergy, whereas TLR4 signaling was dispensable. DEP-induced peanut allergy and Tfh-cell differentiation depended on IL-1 but not IL-33 signaling, whereas neither cytokine alone was necessary for UPM-mediated sensitization. CONCLUSION Environmental co-exposure to peanut and PM induces peanut-specific Tfh cells and peanut allergy in mice.
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Affiliation(s)
- Robert M. Immormino
- Department of Pediatrics, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Johanna M. Smeekens
- Department of Pediatrics, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- UNC Food Allergy Initiative, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Priscilla I. Mathai
- Department of Pediatrics, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Katelyn M. Clough
- University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | | | - Andrew J. Ghio
- Human Studies Facility, United States Environmental Protection Agency, Chapel Hill, North Carolina, USA
| | - Donald N. Cook
- Division of Intramural Research, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, North Carolina, USA
| | - Michael D. Kulis
- Department of Pediatrics, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- UNC Food Allergy Initiative, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Timothy P. Moran
- Department of Pediatrics, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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11
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Zhou Y, Liu K, Tang W, Zhang Y, Sun Y, Wu Y, Shi Y, Yao Z, Li Y, Bai R, Liang R, Sun P, Chang X, Wang S, Zhu Y, Han X. β-Cell miRNA-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and β-Cell Decompensation. Diabetes 2024; 73:57-74. [PMID: 37847900 DOI: 10.2337/db22-1044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 10/02/2023] [Indexed: 10/19/2023]
Abstract
Chronic inflammation promotes pancreatic β-cell decompensation to insulin resistance because of local accumulation of supraphysiologic interleukin 1β (IL-1β) levels. However, the underlying molecular mechanisms remain elusive. We show that miR-503-5p is exclusively upregulated in islets from humans with type 2 diabetes and diabetic rodents because of its promoter hypomethylation and increased local IL-1β levels. β-Cell-specific miR-503 transgenic mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the miR-503 cluster protects mice from high-fat diet-induced insulin resistance and glucose intolerance. Mechanistically, miR-503-5p represses c-Jun N-terminal kinase-interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinase signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory β-cell proliferation. In addition, β-cell miR-503-5p is packaged in nanovesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors. Notably, specifically blocking the miR-503 cluster in β-cells effectively remits aging-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our findings demonstrate that β-cell miR-503-5p is required for the development of insulin resistance and β-cell decompensation, providing a potential therapeutic target against diabetes. ARTICLE HIGHLIGHTS Promoter hypomethylation during natural aging permits miR-503-5p overexpression in islets under inflammation conditions, conserving from rodents to humans. Impaired β-cells release nanovesicular miR-503-5p to accumulate in liver and adipose tissue, leading to their insulin resistance via the miR-503-5p/insulin receptor/phosphorylated AKT axis. Accumulated miR-503-5p in β-cells impairs glucose-stimulated insulin secretion via the JIP2-coordinated mitogen-activated protein kinase signaling cascades. Specific blockage of β-cell miR-503-5p improves β-cell function and glucose tolerance in aging mice.
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Affiliation(s)
- Yuncai Zhou
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kerong Liu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Tang
- Department of Endocrinology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yi Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yangyang Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ying Shi
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhengjian Yao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yating Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rongjie Bai
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Liang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
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12
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Cao K, Liu Z, Liu J, Hu Q, Shan W, Hu B, Shi H, Zhang B. Constitutive photomorphogenic protein 1 ubiquitinates interleukin-1 receptor accessory protein in human liver cancer. J Cancer Res Clin Oncol 2023; 149:16247-16260. [PMID: 37700160 DOI: 10.1007/s00432-023-05367-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 08/29/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Constitutive photomorphogenic protein 1 (COP1) plays a pivotal role in the development and progression of several human cancers and is reported to be upregulated in liver cancer. However, the role of COP1 in human liver cancer is unclear. METHODS We analyzed the COP1 expression in normal liver and liver cancer tissue samples using western blot and immunohistochemical analysis. We overexpressed and silenced COP1 in HepG2 and Huh7 cells and analyzed the effect on liver cancer cell proliferation. Additionally, COP1 was used as a bait to screen COP1-interacting proteins in a human cDNA library in a yeast two-hybrid screen and the results were confirmed with co-immunoprecipitation (co-IP) assays. Moreover, immunofluorescence staining was performed to assess co-localization. The protein levels of COP1 and mIL1RAcP were determined in clinical samples. RESULTS COP1 was upregulated in liver cancer samples compared to that in normal tissue samples. COP1 overexpression promoted proliferation of liver cancer cells, while COP1 knockdown exerted the opposite effect. Yeast two-hybrid screen identified interleukin-1 receptor accessory protein (IL1RAP) as a potential COP1-interacting protein. Co-IP assays further confirmed that COP1 interacts with both preIL1RAP and membrane-bound form of IL1RAP (mIL1RAP). Furthermore, COP1 upregulated mIL1RAP protein levels and promoted nuclear translocation and activation of the nuclear factor kappa B (NF-κB) (p50/p65) dimer. Additionally, we demonstrated that COP1 regulated mIL1RAP expression through K63-linked polyubiquitination, suggesting that COP1 plays a role in stabilizing mIL1RAP. Finally, the protein levels of COP1 and mIL1RAcP were found to be positively correlated in clinical samples. CONCLUSION COP1 regulates IL1RAP, which in turn results in activation of the NF-κB signaling. Our findings suggest that the COP1/IL1RAP/NF-κB axis promotes proliferation of liver cancer cells and is a potential target for the treatment of liver cancer.
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Affiliation(s)
- Kuan Cao
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhiyi Liu
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jin Liu
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Hepatobiliary Pancreatic Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qinghe Hu
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wengang Shan
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bin Hu
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hengliang Shi
- Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Central Laboratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Bin Zhang
- Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
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13
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Zeng X, Liu C, Fan J, Zou J, Guo M, Sun G. RNF138 Downregulates Antiviral Innate Immunity by Inhibiting IRF3 Activation. Int J Mol Sci 2023; 24:16110. [PMID: 38003298 PMCID: PMC10671598 DOI: 10.3390/ijms242216110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
A viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induces type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-β induction. The overexpression of RNF138 inhibited the virus-induced activation of IRF3 and the transcription of the IFNB1 gene, whereas the knockout of RNF138 promoted the virus-induced activation of IRF3 and transcription of the IFNB1 gene. We further found that RNF138 promotes the ubiquitination of PTEN and subsequently inhibits PTEN interactions with IRF3, which is essential for the PTEN-mediated nuclear translocation of IRF3, thereby inhibiting IRF3 import into the nucleus. Our findings suggest that RNF138 negatively regulates virus-triggered signaling by inhibiting the interaction of PTEN with IRF3, and these data provide new insights into the molecular mechanisms of cellular antiviral responses.
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Affiliation(s)
- Xianhuang Zeng
- Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (X.Z.); (J.Z.)
| | - Chaozhi Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China;
| | - Jinhao Fan
- School of Ecology and Environment, Tibet University, Lhasa 850000, China;
| | - Jiabin Zou
- Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (X.Z.); (J.Z.)
| | - Mingxiong Guo
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China;
- School of Ecology and Environment, Tibet University, Lhasa 850000, China;
| | - Guihong Sun
- Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; (X.Z.); (J.Z.)
- Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China
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14
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Liu J, Liu S, Yu M, Li J, Xie Z, Gao B, Liu Y. Anti-inflammatory effect and mechanism of catalpol in various inflammatory diseases. Drug Dev Res 2023; 84:1376-1394. [PMID: 37534768 DOI: 10.1002/ddr.22096] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/21/2023] [Accepted: 07/17/2023] [Indexed: 08/04/2023]
Abstract
Catalpol is a kind of iridoid glucoside, widely found in a variety of plants, mostly extracted from the rhizome of the traditional medicinal herb rehmanniae. It has various biological activities such as anti-inflammatory, antioxidant, and antitumor. The anti-inflammatory effects of catalpol have been demonstrated in a variety of diseases, such as neurological diseases, atherosclerosis, renal diseases, respiratory diseases, digestive diseases, bone and joint diseases, eye diseases, and periodontitis. The purpose of this review is to summarize the existing literature on the anti-inflammatory effects of catalpol in a variety of inflammatory diseases over the last decade and to focus on the anti-inflammatory mechanisms of catalpol.
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Affiliation(s)
- Jinyao Liu
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shuang Liu
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Mingyue Yu
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Jianing Li
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Zunxuan Xie
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Boyang Gao
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Yuyan Liu
- Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun, China
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15
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Affiliation(s)
- Stefanie Steiger
- Renal Division, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
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16
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Ren J, Liu K, Wu B, Lu X, Sun L, Privratsky JR, Xing C, Robson MJ, Mao H, Blakely RD, Abe K, Souma T, Crowley SD. Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI. J Am Soc Nephrol 2023; 34:1629-1646. [PMID: 37545036 PMCID: PMC10561822 DOI: 10.1681/asn.0000000000000191] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 07/02/2023] [Indexed: 08/08/2023] Open
Abstract
SIGNIFICANCE STATEMENT Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. BACKGROUND Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. METHODS To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. RESULTS scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. CONCLUSIONS These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.
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Affiliation(s)
- Jiafa Ren
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Kang Liu
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Buyun Wu
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Xiaohan Lu
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Lianqin Sun
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Jamie R. Privratsky
- Division of Critical Care Medicine, Center for Perioperative Organ Protection, Durham, North Caorlina
- Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
| | - Changying Xing
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Matthew J. Robson
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio
| | - Huijuan Mao
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Randy D. Blakely
- Division of Biomedical Science, Charles E. Schmidt College of Medicine and Stiles-Nicholson FAU Brain Institute, Jupiter, Florida
| | - Koki Abe
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Tomokazu Souma
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Steven D. Crowley
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
- Durham VA Medical Center, Durham, North Carolina
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17
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Feng Y, Chen Z, Xu Y, Han Y, Jia X, Wang Z, Zhang N, Lv W. The central inflammatory regulator IκBζ: induction, regulation and physiological functions. Front Immunol 2023; 14:1188253. [PMID: 37377955 PMCID: PMC10291074 DOI: 10.3389/fimmu.2023.1188253] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
IκBζ (encoded by NFKBIZ) is the most recently identified IkappaB family protein. As an atypical member of the IkappaB protein family, NFKBIZ has been the focus of recent studies because of its role in inflammation. Specifically, it is a key gene in the regulation of a variety of inflammatory factors in the NF-KB pathway, thereby affecting the progression of related diseases. In recent years, investigations into NFKBIZ have led to greater understanding of this gene. In this review, we summarize the induction of NFKBIZ and then elucidate its transcription, translation, molecular mechanism and physiological function. Finally, the roles played by NFKBIZ in psoriasis, cancer, kidney injury, autoimmune diseases and other diseases are described. NFKBIZ functions are universal and bidirectional, and therefore, this gene may exert a great influence on the regulation of inflammation and inflammation-related diseases.
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Affiliation(s)
- Yanpeng Feng
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Zhiyuan Chen
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Yi Xu
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Yuxuan Han
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Xiujuan Jia
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zixuan Wang
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nannan Zhang
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenjing Lv
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
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18
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Riera-Martínez L, Cànaves-Gómez L, Iglesias A, Martin-Medina A, Cosío BG. The Role of IL-33/ST2 in COPD and Its Future as an Antibody Therapy. Int J Mol Sci 2023; 24:ijms24108702. [PMID: 37240045 DOI: 10.3390/ijms24108702] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/28/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
COPD is a leading cause of mortality and morbidity worldwide and is associated with a high socioeconomic burden. Current treatment includes the use of inhaled corticosteroids and bronchodilators, which can help to improve symptoms and reduce exacerbations; however, there is no solution for restoring lung function and the emphysema caused by loss of the alveolar tissue. Moreover, exacerbations accelerate progression and challenge even more the management of COPD. Mechanisms of inflammation in COPD have been investigated over the past years, thus opening new avenues to develop novel targeted-directed therapies. Special attention has been paid to IL-33 and its receptor ST2, as they have been found to mediate immune responses and alveolar damage, and their expression is upregulated in COPD patients, which correlates with disease progression. Here we summarize the current knowledge on the IL-33/ST2 pathway and its involvement in COPD, with a special focus on developed antibodies and the ongoing clinical trials using anti-IL-33 and anti-ST2 strategies in COPD patients.
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Affiliation(s)
- Lluc Riera-Martínez
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
| | - Laura Cànaves-Gómez
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
| | - Amanda Iglesias
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Aina Martin-Medina
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
| | - Borja G Cosío
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Respiratory Medicine, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
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19
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Lee J, Lim JH, Jung GY, Kang J, Jo I, Kang K, Kim JH, Kim BS, Yang H. Triterpenoid saponins from Camellia sinensis roots with cytotoxic and immunomodulatory effects. PHYTOCHEMISTRY 2023; 212:113688. [PMID: 37121294 DOI: 10.1016/j.phytochem.2023.113688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 04/14/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023]
Abstract
Camellia sinensis L. (Theaceae) leaves have been used as a beverage in both Eastern and Western cultures for a long time, while its root has not been intensively studied. In this study, seven undescribed triterpenoid saponins (1-7) and twelve known saponins (8-19) with different combinations of substituents, such as oxygenated isoprenyl substituents and sugar moieties, and lengths of sugar chains, were isolated from the C. sinensis roots. Their structures were unequivocally determined using one- and two-dimensional nuclear magnetic resonance data and acid hydrolysis analysis. Investigation of the biological activities of isolated compounds revealed that only those without functional acetyl groups exhibited cytotoxic activities against mouse and human cancer cells (B16F10) and human cervical cancer cell line (HeLa) at 50 μM. Compounds with an aldehyde group at C-23 of aglycone showed immunomodulatory activity against Th1 and Th17 cells at 10 μM. Ten compounds with biological activities from C. sinensis roots extracts, including three previously undescribed ones (3, 6, and 7), were identified.
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Affiliation(s)
- Jiho Lee
- College of Pharmacy, Kangwon National University, Chuncheon, 24341, South Korea
| | - Jae-Hee Lim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, South Korea
| | - Go-Yeon Jung
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, South Korea
| | - Jeongyeon Kang
- College of Pharmacy, Kangwon National University, Chuncheon, 24341, South Korea
| | - Inhee Jo
- College of Pharmacy, Kangwon National University, Chuncheon, 24341, South Korea
| | - Kiyoon Kang
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, South Korea
| | - Jung-Hwan Kim
- Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, South Korea.
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, South Korea.
| | - Heejung Yang
- College of Pharmacy, Kangwon National University, Chuncheon, 24341, South Korea.
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20
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Guo S, Gao W, Zeng M, Liu F, Yang Q, Chen L, Wang Z, Jin Y, Xiang P, Chen H, Wen Z, Shi Q, Song Z. Characterization of TLR1 and expression profiling of TLR signaling pathway related genes in response to Aeromonas hydrophila challenge in hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂). Front Immunol 2023; 14:1163781. [PMID: 37056759 PMCID: PMC10086376 DOI: 10.3389/fimmu.2023.1163781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Toll‐like receptor 1 (TLR1) mediates the innate immune response to a variety of microbes through recognizing cell wall components (such as bacterial lipoproteins) in mammals. However, the detailed molecular mechanism of TLR1 involved in pathogen immunity in the representative hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂) has not been well studied. In the present study, we identified the TLR1 gene from the hybrid yellow catfish, and further comparative synteny data from multiple species confirmed that the TLR1 gene is highly conserved in teleosts. Phylogenetic analysis revealed distinguishable TLR1s in diverse taxa, suggesting consistence in evolution of the TLR1 proteins with various species. Structural prediction indicated that the three-dimensional structures of TLR1 proteins are relatively conserved among different taxa. Positive selection analysis showed that purifying selection dominated the evolutionary process of TLR1s and TLR1-TIR domain in both vertebrates and invertebrates. Expression pattern analysis based on the tissue distribution showed that TLR1 mainly transcribed in the gonad, gallbladder and kidney, and the mRNA levels of TLR1 in kidney were remarkably up-regulated after Aeromonas hydrophila stimulation, indicating that TLR1 participates in the inflammatory responses to exogenous pathogen infection in hybrid yellow catfish. Homologous sequence alignment and chromosomal location indicated that the TLR signaling pathway is very conserved in the hybrid yellow catfish. The expression patterns of TLR signaling pathway related genes (TLR1- TLR2 - MyD88 - FADD - Caspase 8) were consistent after pathogen stimulation, revealing that the TLR signaling pathway is triggered and activated after A. hydrophila infection. Our findings will lay a solid foundation for better understanding the immune roles of TLR1 in teleosts, as well as provide basic data for developing strategies to control disease outbreak in hybrid yellow catfish.
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Affiliation(s)
- Shengtao Guo
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Wenxue Gao
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Mengsha Zeng
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Fenglin Liu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Qingzhuoma Yang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Lei Chen
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zesong Wang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yanjun Jin
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Peng Xiang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Hanxi Chen
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zhengyong Wen
- Key Laboratory of Sichuan for Fishes Conservation and Utilization in the Upper Reaches of the Yangtze River, College of Life Science, Neijiang Normal University, Neijiang, China
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen, China
- *Correspondence: Zhengyong Wen, ; Qiong Shi, ; Zhaobin Song,
| | - Qiong Shi
- Key Laboratory of Sichuan for Fishes Conservation and Utilization in the Upper Reaches of the Yangtze River, College of Life Science, Neijiang Normal University, Neijiang, China
- Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen, China
- *Correspondence: Zhengyong Wen, ; Qiong Shi, ; Zhaobin Song,
| | - Zhaobin Song
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
- *Correspondence: Zhengyong Wen, ; Qiong Shi, ; Zhaobin Song,
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21
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Mariotti FR, Supino D, Landolina N, Garlanda C, Mantovani A, Moretta L, Maggi E. IL-1R8: A molecular brake of anti-tumor and anti-viral activity of NK cells and ILC. Semin Immunol 2023; 66:101712. [PMID: 36753974 DOI: 10.1016/j.smim.2023.101712] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/30/2022] [Accepted: 01/09/2023] [Indexed: 02/07/2023]
Abstract
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) play pivotal role in immunity and inflammation and are expressed by most cell types including cells of both the innate and adaptive immune system. In this context, IL-1 superfamily members are also important players in regulating function and differentiation of adaptive and innate lymphoid cells. This system is tightly regulated in order to avoid uncontrolled activation, which may lead to detrimental inflammation contributing to autoimmune or allergic responses. IL-1R8 (also known as TIR8 or SIGIRR) is a member of the IL-1R family that acts as a negative regulator dampening ILR and TLR signaling and as a co-receptor for human IL-37. Human and mouse NK cells, that are key players in immune surveillance of tumors and infections, express high level of IL-1R8. In this review, we will summarize our current understanding on the structure, expression and function of IL-1R8 and we will also discuss the emerging role of IL-1R8 as an important checkpoint regulating NK cells function in pathological conditions including cancer and viral infections.
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Affiliation(s)
- Francesca R Mariotti
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy
| | | | - Nadine Landolina
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy
| | - Cecilia Garlanda
- IRCCS, Humanitas Research Hospital, 20089 Rozzano, Italy; Department of Biomedical Science, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Alberto Mantovani
- IRCCS, Humanitas Research Hospital, 20089 Rozzano, Italy; Department of Biomedical Science, Humanitas University, 20072 Pieve Emanuele, Italy; The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Lorenzo Moretta
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy
| | - Enrico Maggi
- Translational Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
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22
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Malkova AM, Gubal AR, Petrova AL, Voronov E, Apte RN, Semenov KN, Sharoyko VV. Pathogenetic role and clinical significance of interleukin-1β in cancer. Immunology 2023; 168:203-216. [PMID: 35462425 DOI: 10.1111/imm.13486] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/28/2022] [Indexed: 01/21/2023] Open
Abstract
In recent years, pro-oncogenic mechanisms of the tumour microenvironment (ТМЕ) have been actively discussed. One of the main cytokines of the TМЕ is interleukin-1 beta (IL-1β), which exhibits proinflammatory properties. Some studies have shown an association between an increase in IL-1β levels and tumour progression. The purpose of this review is to analyse the pathogenic mechanisms induced by IL-1β in the TМЕ, as well as the diagnostic significance of the presence of IL-1β in patients with cancer and the efficacy of treatment with IL-1β inhibitors. According to the literature, IL-1β can induce an increase in tumour angiogenesis due to its effects on the differentiation of epithelial cells, pro-angiogenic molecule secretion and expression of adhesion molecules, thus increasing tumour growth and metastasis. IL-1β is also involved in the suppression of anti-tumour immune responses. The expression and secretion of IL-1β has been noted in various types of tumours. In some clinical studies, an elevated level of IL-1β was found to be associated with low efficacy of anti-cancer therapy and a poor prognosis. In most experimental and clinical studies, the use of IL-1β inhibitors contributed to a decrease in tumour mass and an increase in the response to anti-tumour drugs.
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Affiliation(s)
- Anna M Malkova
- Saint Petersburg State University, Saint Petersburg, Russia.,Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Anna R Gubal
- Saint Petersburg State University, Saint Petersburg, Russia
| | | | - Elena Voronov
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ron N Apte
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Konstantin N Semenov
- Saint Petersburg State University, Saint Petersburg, Russia.,Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.,A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, Saint Petersburg, Russia
| | - Vladimir V Sharoyko
- Saint Petersburg State University, Saint Petersburg, Russia.,Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.,A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, Saint Petersburg, Russia.,Medicinal Chemistry Center, Togliatti State University, Togliatti, Russia
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23
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Wang F, Cui Y, He D, Gong L, Liang H. Natural killer cells in sepsis: Friends or foes? Front Immunol 2023; 14:1101918. [PMID: 36776839 PMCID: PMC9909201 DOI: 10.3389/fimmu.2023.1101918] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Sepsis is one of the major causes of death in the hospital worldwide. The pathology of sepsis is tightly associated with dysregulation of innate immune responses. The contribution of macrophages, neutrophils, and dendritic cells to sepsis is well documented, whereas the role of natural killer (NK) cells, which are critical innate lymphoid lineage cells, remains unclear. In some studies, the activation of NK cells has been reported as a risk factor leading to severe organ damage or death. In sharp contrast, some other studies revealed that triggering NK cell activity contributes to alleviating sepsis. In all, although there are several reports on NK cells in sepsis, whether they exert detrimental or protective effects remains unclear. Here, we will review the available experimental and clinical studies about the opposing roles of NK cells in sepsis, and we will discuss the prospects for NK cell-based immunotherapeutic strategies for sepsis.
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Affiliation(s)
- Fangjie Wang
- State Key Laboratory of Trauma, Burns and Combines Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yiqin Cui
- State Key Laboratory of Trauma, Burns and Combines Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Dongmei He
- State Key Laboratory of Trauma, Burns and Combines Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lisha Gong
- School of Laboratory Medicine and Technology, Harbin Medical University, Daqing, China
| | - Huaping Liang
- State Key Laboratory of Trauma, Burns and Combines Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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24
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Zhou J, Lin H, Lv T, Hao J, Zhang H, Sun S, Yang J, Chi J, Guo H. Inappropriate Activation of TLR4/NF-κB is a Cause of Heart Failure. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2022. [DOI: 10.15212/cvia.2022.0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Significance: Heart failure, a disease with extremely high incidence, is closely associated with inflammation and oxidative stress. The Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway plays an important role in the occurrence and development of heart failure.
Recent advances: Previous studies have shown that TLR4/NF-κB causes heart failure by inducing oxidative stress and inflammation; damaging the endothelia; promoting fibrosis; and inducing myocardial hypertrophy, apoptosis, pyroptosis, and autophagy.
Critical issues: Understanding the pathogenesis of heart failure is essential for the treatment of this disease. In this review, we outline the mechanisms underlying TLR4/NF-κB pathway-mediated heart failure and discuss drugs that alleviate heart failure by regulating the TLR4/NF-κB pathway.
Future directions: During TLR4/NF-κB overactivation, interventions targeting specific receptor antagonists may effectively alleviate heart failure, thus providing a basis for the development of new anti-heart failure drugs.
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Affiliation(s)
- Jiedong Zhou
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Hui Lin
- Department of Cardiology, Shaoxing People’s Hospital Shaoxing Hospital, Shaoxing, China
| | - Tingting Lv
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Jinjin Hao
- Zhejiang University School of Medicine, Hangzhou, China
| | - Hanlin Zhang
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Shimin Sun
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Juntao Yang
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Jufang Chi
- Department of Cardiology, Shaoxing People’s Hospital Shaoxing Hospital, Shaoxing, China
| | - Hangyuan Guo
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
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25
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Abuzeid AMI, Hefni MM, Huang Y, He L, Zhuang T, Li G. Immune pathogenesis in pigeons during experimental Prohemistomum vivax infection. Front Vet Sci 2022; 9:974698. [PMID: 36187827 PMCID: PMC9516004 DOI: 10.3389/fvets.2022.974698] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
Prohemistomum vivax is a small trematode belonging to the family Cyathocotylidae, infecting fish-eating birds and mammals, including humans. However, no data on molecular identification and immune pathogenesis are available, challenging effective diagnostic and therapeutic interventions. Here, we identified P. vivax based on combined morphological and molecular data and examined histopathological lesions and the differential cytokines expression in experimentally infected pigeons. Pigeons were orally infected with 500 prohemistomid metacercariae. Intestinal and spleen tissues were harvested 2, 4, 7, 14, 21, and 28 days post-infection (dpi). Gene expression levels of eleven cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-15, IL-18, IFN-γ, and TGF-β3) were assessed using quantitative reverse-transcription PCR (RT-qPCR). We identified the recovered flukes as Prohemistomum vivax based on morphological features and the sequence and phylogenetic analysis of the internal transcribed spacer 1 (ITS1), 5.8 ribosomal RNA, and ITS2 region. Histopathological lesions were induced as early as 2 dpi, with the intensity of villi atrophy and inflammatory cell infiltration increasing as the infection progressed. An early immunosuppressive state (2 and 4 dpi), with TGF-β3 overexpression, developed to allow parasite colonization. A mixed Th1/Th2 immune response (overexpressed IFN-γ, IL-12, IL-2, IL-4, and IL-5) was activated as the infection progressed from 7 to 28 dpi. Inflammatory cytokines (IL-1, IL-6, IL-18, and IL-15) were generally overexpressed at 7–28 dpi, peaking at 7 or 14 dpi. The upregulated Treg IL-10 expression peaking between 21 and 28 dpi might promote the Th1/Th2 balance and immune homeostasis to protect the host from excessive tissue pathology and inflammation. The intestine and spleen expressed a significantly different relative quantity of cytokines throughout the infection. To conclude, our results presented distinct cytokine alteration throughout P. vivax infection in pigeons, which may aid in understanding the immune pathogenesis and host defense mechanism against this infection.
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Affiliation(s)
- Asmaa M. I. Abuzeid
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Department of Parasitology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Mahmoud M. Hefni
- Institute of Biotechnology for Postgraduates Studies and Researches, Suez Canal University, Ismailia, Egypt
- Mahmoud M. Hefni
| | - Yue Huang
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Long He
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Tingting Zhuang
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Guoqing Li
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- *Correspondence: Guoqing Li
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26
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Li Q, Li R, Yin H, Wang S, Liu B, Li J, Zhou M, Yan Q, Lu L. Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome. Biomed Pharmacother 2022; 153:113459. [PMID: 36076574 PMCID: PMC9339262 DOI: 10.1016/j.biopha.2022.113459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/14/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.
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27
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Joo MS, Choi KM, Kang G, Woo WS, Kim KH, Sohn MY, Son HJ, Han HJ, Choi HS, Kim DH, Park CI. Red sea bream interleukin (IL)-1β and IL-8 expression, subcellular localization, and antiviral activity against red sea bream iridovirus (RSIV). FISH & SHELLFISH IMMUNOLOGY 2022; 128:360-370. [PMID: 35868476 DOI: 10.1016/j.fsi.2022.07.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
Interleukin-1 beta (IL-1β) is transcribed by monocytes, macrophages, and dendritic cells in response to activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) or cytokine signalling and causes a rapid inflammatory response to infection. IL-8, also known as chemokine C-X-C motif ligand (CXCL)-8, is regulated by IL-1β and affects the chemotaxis of macrophages and neutrophils upon pathogen infection. In healthy red sea bream, rsbIL-1β is most highly distributed in the liver, and rsbIL-8 is most highly distributed in the head kidney. In response to RSIV infection, rsbIL-1β and rsbIL-8 mRNA are significantly upregulated in the kidney and spleen. This may be because the primary infection targets of RSIV are the kidney and spleen. In the gills, both genes were significantly upregulated at 7 days after RSIV infection and may be accompanied by a cytokine storm. In the liver, both genes were significantly downregulated at most observation points, which may be because the immune cells such as macrophages and dendritic cells expressing rsbIL-1β or rsbIL-8 migrated to other tissues because the degree of RSIV infection was relatively low. Using a GFP fusion protein, it was confirmed that rsbIL-1β and rsbIL-8 were localized to the cytoplasm of Pagrus major fin (PMF) cells. RsbIL-1β overexpression induced the expression of interferon gamma (IFN-γ), myxovirus-resistance protein (Mx) 1, IL-8, IL-10, TNF-α, and MyD88, while rsbIL-8 overexpression induced the expression of IFN-γ, Mx1, rsbIL-1β and TNF-α. In addition, overexpression of both genes significantly reduced the genome copies of RSIV and significantly reduced the viral titers. Therefore, rsbIL-1β and rsbIL-8 in red sea bream play an antiviral role against RSIV through their normal signalling.
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Affiliation(s)
- Min-Soo Joo
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Kwang-Min Choi
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Gyoungsik Kang
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Won-Sik Woo
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Kyung-Ho Kim
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Min-Young Sohn
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Ha-Jeong Son
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea
| | - Hyun-Ja Han
- Pathology Research Division, National Institute of Fisheries Science, 408-1 Sirang-ri, Gijang-up, Gijang-gun, Busan, 46083, Republic of Korea
| | - Hye-Sung Choi
- Pathology Research Division, National Institute of Fisheries Science, 408-1 Sirang-ri, Gijang-up, Gijang-gun, Busan, 46083, Republic of Korea
| | - Do-Hyung Kim
- Department of Aquatic Life Medicine, College of Fisheries Science, Pukyong National University, 45, Yongso-ro, Nam-Gu, Busan, Republic of Korea.
| | - Chan-Il Park
- Department of Marine Biology & Aquaculture, Institute of Marine Industry, College of Marine Science, Gyeongsang National University, 455, Tongyeong, 650-160, Republic of Korea.
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28
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Ihim SA, Abubakar SD, Zian Z, Sasaki T, Saffarioun M, Maleknia S, Azizi G. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front Immunol 2022; 13:919973. [PMID: 36032110 PMCID: PMC9410767 DOI: 10.3389/fimmu.2022.919973] [Citation(s) in RCA: 132] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/25/2022] [Indexed: 12/13/2022] Open
Abstract
Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectiveness in vitro, in vivo and human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.
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Affiliation(s)
- Stella Amarachi Ihim
- Department of Molecular and Cellular Pharmacology, University of Shizuoka, Shizuoka, Japan
- Department of Pharmacology and Toxicology, University of Nigeria, Nsukka, Nigeria
- Department of Science Laboratory Technology, University of Nigeria, Nsukka, Nigeria
| | - Sharafudeen Dahiru Abubakar
- Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan
- Department of Medical Laboratory Science, College of Medical Science, Ahmadu Bello University, Zaria, Nigeria
| | - Zeineb Zian
- Biomedical Genomics and Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Tetouan, Morocco
| | - Takanori Sasaki
- Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Mohammad Saffarioun
- Biopharmaceutical Research Center, AryoGen Pharmed Inc., Alborz University of Medical Sciences, Karaj, Iran
| | - Shayan Maleknia
- Biopharmaceutical Research Center, AryoGen Pharmed Inc., Alborz University of Medical Sciences, Karaj, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- *Correspondence: Gholamreza Azizi,
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Takeuchi T, Hata T, Miyanishi H, Yuasa T, Setoguchi S, Takeda A, Morimoto N, Hikima JI, Sakai M, Kono T. Diel rhythm of the inflammatory cytokine il1b in the Japanese medaka (Oryzias latipes) regulated by core components of the circadian clock. FISH & SHELLFISH IMMUNOLOGY 2022; 127:238-246. [PMID: 35724845 DOI: 10.1016/j.fsi.2022.06.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/12/2022] [Accepted: 06/14/2022] [Indexed: 06/15/2023]
Abstract
In recent years, studies on circadian control in immunity have been actively conducted in mammals, but little is known about circadian rhythms in the field of fish immunology. In this study, we aimed to analyse the regulation of the diel oscillation of inflammatory cytokine interleukin-1β (il1b) gene expression by core components of the circadian clock in Japanese medaka (Oryzias latipes). The expression of il1b and clock genes (bmal1 and clock1) in medaka acclimated to a 12:12 light (L): dark (D) cycle showed diel rhythm. Additionally, higher expression of il1b was detected in medaka embryo cells (OLHdrR-e3) overexpressing bmal1 and clock1. A significant decrease in il1b expression was observed in OLHdrR-e3 cells after bmal1 knockdown using morpholino oligos. These changes may be mediated by transcriptional regulation via clock proteins, which target the E-box sequence in the cis-element of il1b as identified using luciferase reporter assays. Moreover, LPS stimulation and pathogenic bacterial infection at different zeitgeber time (ZT) under LD12:12 conditions affected the degree of il1b expression, which showed high and low responsiveness to both immuno-stimulations at ZT2 and ZT14, respectively. These results suggested that fish IL-1β exhibited diel oscillation regulated by clock proteins, and its responsiveness to immune-stimulation depends on the time of day.
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Affiliation(s)
- Tomoya Takeuchi
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Takahiko Hata
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Hiroshi Miyanishi
- Department of Marine Biology and Environmental Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
| | - Takumi Yuasa
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Suzuka Setoguchi
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Ayaka Takeda
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Natsuki Morimoto
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Jun-Ichi Hikima
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Masahiro Sakai
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan
| | - Tomoya Kono
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen Kibanadai-nishi, Miyazaki, 889-2192, Japan.
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Ji NN, Xia M. Enriched environment alleviates adolescent visceral pain, anxiety- and depression-like behaviors induced by neonatal maternal separation. Transl Pediatr 2022; 11:1398-1407. [PMID: 36072545 PMCID: PMC9442205 DOI: 10.21037/tp-22-410] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Neonatal maternal separation (NMS), a major kind of early life stress, increases the risk of visceral pain, anxiety- and depression-like behaviors in adulthood. An enriched environment (EE) has been shown to successfully rescue the brain from various early life psychological stressors. Therefore, this study aimed to investigate whether NMS induces visceral pain, anxiety- and depression-like behaviors in adolescents and to evaluate the impact of EE in infancy on these symptoms. METHODS Male C57BL/6 J mice that had been subjected to NMS were used in this study. The visceral pain threshold test (PTT), open field test (OFT), and sucrose preference test (SPT) were conducted to evaluate visceral pain, anxiety- and depression-like behaviors in mice, respectively. An enzyme linked immunosorbent assay (ELISA) for tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), and interleukin-10 (IL-10) was performed to assess neuroinflammatory responses. Then, the effects of EE (free-turning running wheels, pipes, stairs, and various colored ocean balls, etc.) on NMS-induced behaviors and neuroinflammatory factors were examined. RESULTS The impacts of NMS included adolescent visceral pain, anxiety- and depression-like behaviors. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and paraventricular nucleus (PVN) were biased towards pro-inflammatory features. Further, EE alleviated adolescent visceral pain, anxiety- and depression-like behaviors. The application of EE up-regulated the expression of IL-10, and down-regulated the expression of IL-1β and TNF-α in mPFC, BLA, and PVN. CONCLUSIONS The effects of NMS include adolescent visceral pain, anxiety- and depression-like behaviors, accompanied by an imbalance of neuroinflammation. Intervention with EE in pediatric mice relieved these symptoms by reducing neuroinflammation in the central nervous system.
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Affiliation(s)
- Ning-Ning Ji
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Ming Xia
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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31
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Liu N, Chen H, Wang X, Wang D, Fu ZQ. TIRggering cell death via two enzymatic reactions. MOLECULAR PLANT 2022; 15:1263-1265. [PMID: 35808828 DOI: 10.1016/j.molp.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/28/2022] [Accepted: 07/06/2022] [Indexed: 06/15/2023]
Affiliation(s)
- Na Liu
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Huan Chen
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Xu Wang
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Daowen Wang
- State Key Laboratory of Wheat and Maize Crop Science, College of Agronomy, Center for Crop Genome Engineering, Henan Agricultural University, Zhengzhou 450002, China.
| | - Zheng Qing Fu
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
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Esposito P, Kearns MM, Smith KB, Chandrasegaram R, Kadamani AK, Gandelman M, Liang J, Nikpoor N, Tompkins TA, Ismail N. The effects of antimicrobials and lipopolysaccharide on acute immune responsivity in pubertal male and female CD1 mice. COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY 2022; 11:100147. [PMID: 35967925 PMCID: PMC9363646 DOI: 10.1016/j.cpnec.2022.100147] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/26/2022] [Accepted: 05/30/2022] [Indexed: 11/18/2022] Open
Abstract
Exposure to stress during critical periods of development—such as puberty—is associated with long-term disruptions in brain function and neuro-immune responsivity. However, the mechanisms underlying the effect of stress on the pubertal neuro-immune response has yet to be elucidated. Therefore, the objective of the current study was to investigate the effect antimicrobial and lipopolysaccharide (LPS) treatments on acute immune responsivity in pubertal male and female mice. Moreover, the potential for probiotic supplementation to mitigate these effects was also examined. 240 male and female CD1 mice were treated with one week of antimicrobial treatment (mixed antimicrobials or water) and probiotic treatment (L. rhamnosis R0011 and L. helveticus R0052 or L. helveticus R0052 and B. longum R0175) or placebo at five weeks of age. At six weeks of age (pubertal stress-sensitive period), the mice received a single injection of LPS or saline. Sickness behaviours were assessed, and mice were euthanized 8 h post-injection. Brain, blood, and intestinal samples were collected. The results indicated that the antimicrobial treatment reduced sickness behaviours, and potentiated LPS-induced plasma cytokine concentrations and pro-inflammatory markers in the pre-frontal cortex (PFC) and hippocampus, in a sex-dependent manner. However, probiotics reduced LPS-induced plasma cytokine concentrations along with hippocampal and PFC pro-inflammatory markers in a sex-dependent manner. L. rhamnosis R0011 and L. helveticus R0052 treatment also mitigated antimicrobial-induced plasma cytokine concentrations and sickness behaviours. These findings suggest that the microbiome is an important modulator of the pro-inflammatory immune response during puberty.
Pubertal dysbiosis increases LPS-induced neuroinflammation. Pubertal dysbiosis increases LPS-induced plasma cytokine concentrations. Pubertal probiotic treatment reduces LPS-induced neuroinflammation. Pubertal probiotic treatment reduces LPS-induced plasma cytokine concentrations. Pubertal probiotic treatment reduces LPS-induced sickness.
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Gupta M, Chandan K, Sarwat M. Natural Products and their Derivatives as Immune Check Point Inhibitors: Targeting Cytokine/Chemokine Signalling in Cancer. Semin Cancer Biol 2022; 86:214-232. [PMID: 35772610 DOI: 10.1016/j.semcancer.2022.06.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/15/2022] [Accepted: 06/24/2022] [Indexed: 11/29/2022]
Abstract
Cancer immunotherapy is the new generation and widely accepted form of tumour treatment. It is, however, associated with exclusive challenges which include organ-specific inflammation, and single-target strategies. Therefore, approaches that can enhance the efficiency of existing immunotherapies and expand their indications are required for the further development of immunotherapy. Natural products and medicines are stated to have this desired effect on cancer immunotherapy (adoptive immune-cells therapy, cancer vaccines, and immune-check point inhibitors). They refurbish the immunosuppressed tumour microenvironment, which is the primary location of interaction of tumour cells with the host immune system. Various immune cell subsets, via interaction with cytokine/chemokine receptors, are recruited into this microenvironment, and these subsets have roles in tumour progression and treatment responsiveness. This review summarises cytokine/chemokine signalling, types of cancer immunotherapy and the herbal medicine-derived natural products targeting cytokine/chemokines and immune checkpoints. These natural compounds possess immunomodulatory activities and exert their anti-tumour effect by either blocking the interaction or modulating the expression of the proteins linked with immune checkpoint signaling pathways. Some compounds also show a synergistic effect in combination with existing monoclonal antibody drugs to reverse the tumour microenvironment. Additionally, we have also reported some studies about the derivatives and formulations used to overcome the limitations of natural forms. This review can provide important insights for directing future research.
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Affiliation(s)
- Meenakshi Gupta
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
| | - Kumari Chandan
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India.
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34
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Evavold CL, Kagan JC. Diverse Control Mechanisms of the Interleukin-1 Cytokine Family. Front Cell Dev Biol 2022; 10:910983. [PMID: 35832789 PMCID: PMC9272893 DOI: 10.3389/fcell.2022.910983] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/17/2022] [Indexed: 11/15/2022] Open
Abstract
The majority of interleukin-1 (IL-1) family cytokines lack amino terminal secretion signals or transmembrane domains for secretion along the conventional biosynthetic pathway. Yet, these factors must be translocated from the cytoplasm across the plasma membrane into the extracellular space in order to regulate inflammation. Recent work has identified an array of mechanisms by which IL-1 family cytokines can be released into the extracellular space, with supramolecular organizing centers known as inflammasomes serving as dominant drivers of this process. In this review, we discuss current knowledge of the mechanisms of IL-1 family cytokine synthesis, processing, and release from cells. Using this knowledge, we propose a model whereby host metabolic state dictates the route of IL-1β secretion, with implications for microbial infection and sterile inflammation.
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Affiliation(s)
- Charles L. Evavold
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States
- *Correspondence: Charles L. Evavold, ; Jonathan C. Kagan,
| | - Jonathan C. Kagan
- Division of Gastroenterology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
- *Correspondence: Charles L. Evavold, ; Jonathan C. Kagan,
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Pretre V, Papadopoulos D, Regard J, Pelletier M, Woo J. Interleukin-1 (IL-1) and the inflammasome in cancer. Cytokine 2022; 153:155850. [PMID: 35279620 DOI: 10.1016/j.cyto.2022.155850] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/13/2022] [Accepted: 03/03/2022] [Indexed: 12/14/2022]
Abstract
Numerous preclinical and clinical studies have demonstrated the significant contribution of inflammation to the development and progression of various types of cancer. Inflammation in the tumor microenvironment mediates complex interactions between innate immunity, adaptive immunity, microbiomes and stroma, and ultimately alters the overall fitness of tumor cells at multiple stages of carcinogenesis. Malignancies are known to arise in areas of chronic inflammation and inflammation in the tumor microenvironment (often called tumor-promoting inflammation) is believed to allow cancer cells to evade immunosurveillance while promoting genetic instability, survival and progression. Among the strongest data suggesting a causal role for inflammation in cancer come from the recent CANTOS trial which demonstrated that interleukin-1β (IL-1β) inhibition with canakinumab leads to a significant, dose-dependent decrease in incident lung cancer. This observation has launched a series of additional clinical studies to understand the role of IL-1β and the inflammasome in cancer, and the clinical utility of IL-1β inhibition in different stages of lung cancer. In this article we will review recent data implicating IL-1β signaling and its upstream regulator NLRP3 in both solid tumor and hematologic malignancies. We will discuss the key preclinical observations and the current clinical landscape, and describe the pharmacologic tools which will be used to evaluate the effects of blocking tumor-promoting inflammation clinically.
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Sun R, Gao DS, Shoush J, Lu B. The IL-1 family in tumorigenesis and antitumor immunity. Semin Cancer Biol 2022; 86:280-295. [DOI: 10.1016/j.semcancer.2022.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/24/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022]
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Titi-Lartey O, Mohammed I, Amoaku WM. Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases. FRONTIERS IN OPHTHALMOLOGY 2022; 2:850394. [PMID: 38983565 PMCID: PMC11182157 DOI: 10.3389/fopht.2022.850394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/08/2022] [Indexed: 07/11/2024]
Abstract
There is growing evidence that the pathogenesis of retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) have a significant chronic inflammatory component. A vital part of the inflammatory cascade is through the activation of pattern recognition receptors (PRR) such as toll-like receptors (TLR). Here, we reviewed the past and current literature to ascertain the cumulative knowledge regarding the effect of TLRs on the development and progression of retinal diseases. There is burgeoning research demonstrating the relationship between TLRs and risk of developing retinal diseases, utilising a range of relevant disease models and a few large clinical investigations. The literature confirms that TLRs are involved in the development and progression of retinal diseases such as DR, AMD, and ischaemic retinopathy. Genetic polymorphisms in TLRs appear to contribute to the risk of developing AMD and DR. However, there are some inconsistencies in the published reports which require further elucidation. The evidence regarding TLR associations in retinal dystrophies including retinitis pigmentosa is limited. Based on the current evidence relating to the role of TLRs, combining anti-VEGF therapies with TLR inhibition may provide a longer-lasting treatment in some retinal vascular diseases.
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Affiliation(s)
| | | | - Winfried M. Amoaku
- Academic Ophthalmology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
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Luís JP, Mata AI, Simões CJV, Brito RMM. Analysis of the Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Rearrangements. Int J Mol Sci 2022; 23:ijms23052599. [PMID: 35269739 PMCID: PMC8910350 DOI: 10.3390/ijms23052599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 12/24/2022] Open
Abstract
Interleukin-1 receptor type 1 (IL-1R1) is a key player in inflammation and immune responses. This receptor regulates IL-1 activity in two forms: as a membrane-bound form and as a soluble ectodomain. The details and differences between the conformational dynamics of the membrane-bound and the soluble IL-1R1 ectodomains (ECDs) remain largely elusive. Here, we study and compare the structural dynamics of the soluble and membrane-bound IL-1R1-ECDs using molecular dynamics (MD) simulations, focusing on the flexible interdomain linker of the ECD, as well as the spatial rearrangements between the Ig-like domains of the ECD. To explore the membrane-bound conformations, a full-length IL-1R1 structural model was developed and subjected to classical equilibrium MD. Comparative analysis of multiple MD trajectories of the soluble and the membrane-bound IL-1R1-ECDs reveals that (i) as somewhat expected, the extent of the visited “open-to-closed” transitional states differs significantly between the soluble and membrane-bound forms; (ii) the soluble form presents open-closed transitions, sampling a wider rotational motion between the Ig-like domains of the ECD, visiting closed and “twisted” conformations in higher extent, whereas the membrane-bound form is characterized by more conformationally restricted states; (iii) interestingly, the backbone dihedral angles of residues Glu202, Glu203 and Asn204, located in the flexible linker, display the highest variations during the transition between discrete conformational states detected in IL-1R1, thus appearing to work as the “central wheel of a clock’s movement”. The simulations and analyses presented in this contribution offer a deeper insight into the structure and dynamics of IL-1R1, which may be explored in a drug discovery setting.
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Affiliation(s)
- João P. Luís
- Coimbra Chemistry Center—Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal; (A.I.M.); (C.J.V.S.)
- Correspondence: (J.P.L.); (R.M.M.B.)
| | - Ana I. Mata
- Coimbra Chemistry Center—Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal; (A.I.M.); (C.J.V.S.)
| | - Carlos J. V. Simões
- Coimbra Chemistry Center—Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal; (A.I.M.); (C.J.V.S.)
- BSIM Therapeutics, Instituto Pedro Nunes, 3030-199 Coimbra, Portugal
| | - Rui M. M. Brito
- Coimbra Chemistry Center—Institute of Molecular Sciences (CQC-IMS), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal; (A.I.M.); (C.J.V.S.)
- BSIM Therapeutics, Instituto Pedro Nunes, 3030-199 Coimbra, Portugal
- Correspondence: (J.P.L.); (R.M.M.B.)
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ElSayed S, Jay GD, Cabezas R, Qadri M, Schmidt TA, Elsaid KA. Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs. Front Immunol 2022; 12:771677. [PMID: 34992596 PMCID: PMC8725049 DOI: 10.3389/fimmu.2021.771677] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/30/2021] [Indexed: 12/15/2022] Open
Abstract
Objectives To compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes. Methods Acute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed. Results Enhanced phagocytic activation of gout monocytes under basal conditions (p<0.001) was associated with ROS generation and MSU stimulated IL-1β secretion (p<0.05). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion (p<0.05). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes (p<0.05). PP2A inhibition reversed rhPRG4’s effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice (p<0.01) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx (p<0.05). Conclusions MSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and in vivo, PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.
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Affiliation(s)
- Sandy ElSayed
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, United States
| | - Gregory D Jay
- Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, United States
| | - Ralph Cabezas
- Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, United States
| | - Marwa Qadri
- Department of Pharmacology, School of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Tannin A Schmidt
- Biomedical Engineering Department, University of Connecticut Health Center, Farmington, CT, United States
| | - Khaled A Elsaid
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, United States
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Network Pharmacology- and Molecular Docking-Based Identification of Potential Phytocompounds from Argyreia capitiformis in the Treatment of Inflammation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8037488. [PMID: 35140801 PMCID: PMC8820870 DOI: 10.1155/2022/8037488] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/03/2022] [Accepted: 01/15/2022] [Indexed: 12/16/2022]
Abstract
The methanolic extract of Argyreia capitiformis stem was examined for anti-inflammatory activities following network pharmacology analysis and molecular docking study. Based on gas chromatography-mass spectrometry (GC-MS) analysis, 49 compounds were identified from the methanolic extract of A. capitiformis stem. A network pharmacology analysis was conducted against the identified compounds, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology analysis of biological processes and molecular functions were performed. Six proteins (IL1R1, IRAK4, MYD88, TIRAP, TLR4, and TRAF6) were identified from the KEGG pathway analysis and subjected to molecular docking study. Additionally, six best ligand efficiency compounds and positive control (aspirin) from each protein were evaluated for their stability using the molecular dynamics simulation study. Our study suggested that IL1R1, IRAK4, MYD88, TIRAP, TLR4, and TRAF6 proteins may be targeted by compounds in the methanolic extract of A. capitiformis stem to provide anti-inflammatory effects.
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Ren J, Lu X, Hall G, Privratsky JR, Robson MJ, Blakely RD, Crowley SD. IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage. Am J Physiol Renal Physiol 2022; 322:F164-F174. [PMID: 34894725 PMCID: PMC8782651 DOI: 10.1152/ajprenal.00353.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/22/2021] [Accepted: 12/07/2021] [Indexed: 02/03/2023] Open
Abstract
Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.
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Affiliation(s)
- Jiafa Ren
- Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaohan Lu
- Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
| | - Gentzon Hall
- Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
| | - Jamie R Privratsky
- Department of Anesthesiology, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
| | - Matthew J Robson
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio
| | - Randy D Blakely
- Department of Biomedical Science, Charles E. Schmidt College of Medicine and FAU Brain Institute, Jupiter, Florida
| | - Steven D Crowley
- Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
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Xie J, Zhang Y, Jiang L. Role of Interleukin-1 in the pathogenesis of colorectal cancer: A brief look at anakinra therapy. Int Immunopharmacol 2022; 105:108577. [PMID: 35121226 DOI: 10.1016/j.intimp.2022.108577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/16/2022] [Accepted: 01/23/2022] [Indexed: 12/21/2022]
Abstract
Colorectal cancer (CRC) is known as one of the deadliest and most common cancers globally and causes nearly one million cancer deaths yearly. Like many malignancies, the immune system and its components play a crucial role in the pathogenesis of CRC. As multifunction mediators of the immune system, cytokines are involved in several inflammatory and anti-inflammatory responses. Interleukin-1 (IL-1) belongs to a family of 11 members and is involved in inflammatory responses. Beyond its biological role as a mediator of innate immune responses, it is also seen in chronic stress and inflammation and numerous pathological states. The role of IL-1 in malignancies can also be very significant because it has recently been shown that this cytokine can also be secreted from tumor cells and induce the recruitment of myeloid-derived immunosuppressive cells. As a result, the tumor microenvironment (TME) is affected and, despite being inflammatory, causes the onset and progression of tumor cells. Since surgery and chemotherapy are the first choices to treat patients with cancer, especially CRC, it is usually not well-prognosed, particularly in patients with metastatic lesions CRC. Therefore, targeted therapy may prolong the overall survival of CRC patients. Furthermore, evidence shows that anakinra has had satisfactory results in treating CRC. Therefore, this review summarized the role of IL-1 in the pathogenesis of CRC as well as immunotherapy based on inhibition of this cytokine in this type of cancer.
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Affiliation(s)
- Jun Xie
- Department of Colorectal Surgery, Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, China
| | - Yu Zhang
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014,Zhejiang, China
| | - Luxi Jiang
- Laboratory Medicine Center, Department of Transfusion Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
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Banete A, Barilo J, Whittaker R, Basta S. The Activated Macrophage - A Tough Fortress for Virus Invasion: How Viruses Strike Back. Front Microbiol 2022; 12:803427. [PMID: 35087503 PMCID: PMC8787342 DOI: 10.3389/fmicb.2021.803427] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/06/2021] [Indexed: 12/29/2022] Open
Abstract
Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.
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Affiliation(s)
- Andra Banete
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.,Department of Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
| | - Julia Barilo
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Reese Whittaker
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Sameh Basta
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
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Akhter J, Khan J, Baghel M, Beg MMA, Goswami P, Afjal MA, Ahmad S, Habib H, Najmi AK, Raisuddin S. NLRP3 inflammasome in rosmarinic acid-afforded attenuation of acute kidney injury in mice. Sci Rep 2022; 12:1313. [PMID: 35079027 PMCID: PMC8789898 DOI: 10.1038/s41598-022-04785-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/31/2021] [Indexed: 12/15/2022] Open
Abstract
Cisplatin (CP) is a well-known anticancer drug used to effectively treat various kinds of solid tumors. CP causes acute kidney injury (AKI) and unfortunately, there is no therapeutic approach in hand to prevent AKI. Several signaling pathways are responsible for inducing AKI which leads to inflammation in proximal convoluted tubule cells in the kidney. Furthermore, the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is involved in the CP-induced AKI. In this study, we investigated therapeutic effects of rosmarinic acid (RA) against inflammation-induced AKI. RA was orally administered at the dose of 100 mg/kg for two consecutive days after 24 h of a single injection of CP at the dose of 20 mg/kg administered intraperitoneally in Swiss albino male mice. Treatment of RA inhibited the activation of NLRP3 signaling pathway by blocking the activated caspase-1 and downstream signal molecules such as IL-1β and IL18. CP activated HMGB1-TLR4/MyD88 axis was also found to be downregulated with the RA treatment. Activation of nuclear factor-κB and elevated protein expression of cyclooxygenase-2 (COX-2) were also found to be downregulated in RA-treated animals. Alteration of early tubular injury biomarker, kidney injury molecule-1 (KIM-1), was found to be subsided in RA-treated mice. RA has been earlier reported for antioxidant and anti-inflammatory properties. Our findings show that blocking a critical step of inflammasome signaling pathway by RA treatment can be a novel and beneficial approach to prevent the CP-induced AKI.
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Affiliation(s)
- Juheb Akhter
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
| | - Jasim Khan
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Madhu Baghel
- Metabolic Research Laboratory, National Institute of Immunology, New Delhi, 110067, India
| | - Mirza Masroor Ali Beg
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
| | - Poonam Goswami
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
| | - Mohd Amir Afjal
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
| | - Shahzad Ahmad
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
| | - Haroon Habib
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Sheikh Raisuddin
- Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India.
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Wierzbicka JM, Piotrowska A, Purzycka-Bohdan D, Olszewska A, Nowak JI, Szczerkowska-Dobosz A, Nedoszytko B, Nowicki RJ, Żmijewski MA. The Effects of Vitamin D on the Expression of IL-33 and Its Receptor ST2 in Skin Cells; Potential Implication for Psoriasis. Int J Mol Sci 2021; 22:12907. [PMID: 34884710 PMCID: PMC8657669 DOI: 10.3390/ijms222312907] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 11/29/2022] Open
Abstract
Interleukin 33 (IL-33) belongs to the IL-1 family and is produced constitutively by epithelial and endothelial cells of various organs, such as the skin. It takes part in the maintenance of tissue homeostasis, repair, and immune response, including activation of Th2 lymphocytes. Its involvement in pathogenesis of several inflammatory diseases including psoriasis was also suggested, but this is not fully understood. The aim of the study was to investigate expression of IL-33 and its receptor, ST2, in psoriasis, and the effects of the active form of vitamin D (1,25(OH)2D3) on their expression in skin cells. Here we examined mRNA and protein profiles of IL-33 and ST2 in 18 psoriatic patients and healthy volunteers by qPCR and immunostaining techniques. Potential effects of 1,25(OH)2D3 and its receptor (VDR) on the expression of IL-33 and ST2 were tested in cultured keratinocytes, melanocytes, fibroblasts, and basal cell carcinoma cells. It was shown that 1,25(OH)2D3 effectively stimulated expression of IL-33 and its receptor ST2's mRNAs in a time-dependent manner, in keratinocytes and to the lesser extends in melanocytes, but not in fibroblasts. Furthermore, the effect of vitamin D on expression of IL-33 and ST2 was VDR-dependent. Finally, we demonstrated that the expression of mRNA for IL-33 was mainly elevated in the psoriatic skin but not in its margin. Interestingly, ST2 mRNA was downregulated in psoriatic lesion compared to both marginal tissue as well as healthy skin. Our data indicated that vitamin D can modulate IL-33 signaling, opening up new perspectives for our understanding of the mechanism of vitamin D action in psoriasis therapy.
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Affiliation(s)
- Justyna M. Wierzbicka
- Histology Department, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland; (J.M.W.); (A.P.); (A.O.); (J.I.N.)
| | - Anna Piotrowska
- Histology Department, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland; (J.M.W.); (A.P.); (A.O.); (J.I.N.)
| | - Dorota Purzycka-Bohdan
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland; (D.P.-B.); (A.S.-D.); (B.N.); (R.J.N.)
| | - Anna Olszewska
- Histology Department, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland; (J.M.W.); (A.P.); (A.O.); (J.I.N.)
| | - Joanna I. Nowak
- Histology Department, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland; (J.M.W.); (A.P.); (A.O.); (J.I.N.)
| | - Aneta Szczerkowska-Dobosz
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland; (D.P.-B.); (A.S.-D.); (B.N.); (R.J.N.)
| | - Bogusław Nedoszytko
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland; (D.P.-B.); (A.S.-D.); (B.N.); (R.J.N.)
- Invicta Fertility and Reproductive Centre, Molecular Laboratory, 80-850 Gdansk, Poland
| | - Roman J. Nowicki
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland; (D.P.-B.); (A.S.-D.); (B.N.); (R.J.N.)
| | - Michał A. Żmijewski
- Histology Department, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland; (J.M.W.); (A.P.); (A.O.); (J.I.N.)
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Immunosuppression in Rheumatologic and Auto-immune Disease. Handb Exp Pharmacol 2021; 272:181-208. [PMID: 34734308 DOI: 10.1007/164_2021_551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Many rheumatologic diseases are thought to originate in dysregulation of the immune system; lupus nephritis, for example, involves humoral immunity, while autoinflammatory diseases such as familial Mediterranean fever are caused by defects in innate immunity. Of note, this dysregulation may involve both upregulation of immune system components and aspects of immunodeficiency. Treatment of rheumatologic diseases thus requires a familiarity with a variety of immunosuppressive medications and their effects on immune system function.In many rheumatologic conditions, due to an incompletely elucidated mechanism of disease, immunosuppression is relatively broad in contrast to agents used, for example, in treatment of transplant rejection. Multiple immunosuppressive drugs may also be used in succession or in combination. As such, an understanding of the mechanisms and targets of immunosuppressive drugs is essential to appreciating their utility and potential adverse effects. Because of the overlap between therapies used in rheumatologic as well as other inflammatory disorders, some of these medications are discussed in other disease processes (e.g., Immunosuppression for inflammatory bowel disease) or in greater detail in other chapters of this textbook (corticosteroids, mTOR inhibitors, antiproliferative agents).
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Dubuisson N, Versele R, Davis-López de Carrizosa MA, Selvais CM, Brichard SM, Abou-Samra M. Walking down Skeletal Muscle Lane: From Inflammasome to Disease. Cells 2021; 10:cells10113023. [PMID: 34831246 PMCID: PMC8616386 DOI: 10.3390/cells10113023] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/14/2022] Open
Abstract
Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 (NLRP3) inflammasome is probably the best characterized. To date, NLRP3 has been extensively studied in the heart, where its effects and actions have been broadly documented in numerous cardiovascular diseases. However, little is still known about NLRP3 implications in muscle disorders affecting non-cardiac muscles. In this review, we summarize and present the current knowledge regarding the function of NLRP3 in diseased skeletal muscle, and discuss the potential therapeutic options targeting the NLRP3 inflammasome in muscle disorders.
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Affiliation(s)
- Nicolas Dubuisson
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
- Neuromuscular Reference Center, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
- Correspondence:
| | - Romain Versele
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
| | - María A. Davis-López de Carrizosa
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, 41012 Seville, Spain
| | - Camille M. Selvais
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
| | - Sonia M. Brichard
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
| | - Michel Abou-Samra
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
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Li X, Ma L, Wei Y, Gu J, Liang J, Li S, Cui Y, Liu R, Huang H, Yang C, Zhou H. Cabozantinib ameliorates lipopolysaccharide-induced lung inflammation and bleomycin--induced early pulmonary fibrosis in mice. Int Immunopharmacol 2021; 101:108327. [PMID: 34741997 DOI: 10.1016/j.intimp.2021.108327] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 10/19/2022]
Abstract
The lung, as the primary organ for gas exchange in mammals, is the main target organ for many pathogens and allergens, which may cause acute lung injury. A certain proportion of acute lung injury may progress into irreversible pulmonary fibrosis. Both acute lung injury and pulmonary fibrosis have high mortality rates and few effective treatments. Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor and has been approved for the treatment of multiple malignant solid tumors. In this study, we explored the role of cabozantinib in acute lung injury and pulmonary fibrosis in vivo and in vitro. In the lipopolysaccharide and bleomycin induced mouse lung injury models, cabozantinib significantly improved the pathological state and reduced the infiltration of inflammatory cells in the lung tissues. In the bleomycin induced pulmonary fibrosis model, cabozantinib significantly reduced the area of pulmonary fibrosis and improved lung function in mice. The results of in vitro studies showed that cabozantinib could inhibit the inflammatory response and apoptosis of alveolar epithelial cells by inhibiting the activation of TLR4/NF-κB and NLRP3 inflammasome pathways. At the same time, cabozantinib could inhibit the activation of lung fibroblasts through suppressing the TGF-β1/Smad pathway, and promote the apoptosis of fibroblasts. In summary, cabozantinib could alleviate lung injury through regulating the TLR4 /NF-κB/NLRP3 inflammasome pathway, and alleviate pulmonary fibrosis by inhibiting the TGF-β1/Smad3 signaling pathway.
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Affiliation(s)
- Xiaohe Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China
| | - Ling Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China
| | - Yuli Wei
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China
| | - Jinying Gu
- Tianjin Jikun Technology Co., Ltd. Tianjin 301700, People's Republic of China
| | - Jingjing Liang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China
| | - Shimeng Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China
| | - Yunyao Cui
- Tianjin Jikun Technology Co., Ltd. Tianjin 301700, People's Republic of China
| | - Rui Liu
- Tianjin Jikun Technology Co., Ltd. Tianjin 301700, People's Republic of China
| | - Hui Huang
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People's Republic of China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China
| | - Honggang Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China.
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Ferreira ÉC, Oliveira ACDR, Garcia CG, Cossenza M, Gonçalves-de-Albuquerque CF, Castro-Faria-Neto HC, Giestal-de-Araujo E, Dos Santos AA. PMA treatment fosters rat retinal ganglion cell survival via TNF signaling. Neurosci Lett 2021; 763:136197. [PMID: 34437989 DOI: 10.1016/j.neulet.2021.136197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 10/20/2022]
Abstract
An insult can trigger a protective response or even cell death depending on different factors that include the duration and magnitude of the event and the ability of the cell to activate protective intracellular signals, including inflammatory cytokines. Our previous work showed that the treatment of Lister Hooded rat retinal cell cultures with 50 ng/mL phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, increases the survival of retinal ganglion cells (RGCs) kept in culture for 48 h after axotomy. Here we aim to analyze how PMA modulates the levels of TNF-α and IL-1β (both key inflammatory mediators) and the impact of this modulation on RGCs survival. We hypothesize that the increase in RGCs survival mediated by PMA treatment depends upon modulation of the levels of IL-1β and TNF-α. The effect of PMA treatment was assayed on cell viability, caspase 3 activation, TNF-α and IL-1β release and TNF receptor type I (TNFRI) and TNF receptor type II (TNFRII) levels. PMA treatment increases IL-1β and TNF-α levels in 15 min in culture and increases the release of both cytokines after 30 min and 24 h, respectively. Both IL-1β and TNF-α levels decrease after 48 h of PMA treatment. PMA treatment also induces an increase in TNFRII levels while decreasing TNFRI after 24 h. PMA also inhibited caspase-3 activation, and decreased ROS production and EthD-1/calcein ratio in retinal cell cultures leading to an increase in cell viability. The neutralization of IL-1β (anti-IL1β 0,1ng/mL), the neutralization of TNF-α (anti-TNF-α 0,1ng/mL) and the TNF-α inhibition using a recombinant soluble TNFRII abolished PMA effect on RGCs survival. These data suggest that PMA treatment induces IL1β and TNF-α release and modulation of TNFRI/TNFRII expression promoting RGCs survival after axotomy.
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Affiliation(s)
- Érica Camila Ferreira
- Programa de Pós-Graduação em Neurociências, Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | | | - Carlos Gustavo Garcia
- Programa de Pós-Graduação em Neurociências, Universidade Federal Fluminense, Rio de Janeiro, Brazil; Universidade Anhanguera, Av. Visconde do Rio Branco, 123, Niterói, Rio de Janeiro CEP 24020-000, Brazil
| | - Marcelo Cossenza
- Programa de Pós-Graduação em Neurociências, Universidade Federal Fluminense, Rio de Janeiro, Brazil; Departamento de Fisiologia e Farmacologia, Laboratório de Interações Neuroquímicas e Laboratório de Farmacologia Molecular, Instituto Biomédico, Universidade Federal Fluminense, Niterói, Rio de Janeiro CEP: 24020-150, Brazil
| | - Cassiano Felippe Gonçalves-de-Albuquerque
- Programa de Pós-Graduação em Neurociências, Universidade Federal Fluminense, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC/Fiocruz), Rio de Janeiro CEP 21040900, Brazil; Departamento de Bioquímica - Laboratório de Imunofarmacologia, Instituto Biomédico, UNIRIO Rua Frei Caneca 94, Rio de Janeiro, RJ CEP 20211030, Brazil
| | - Hugo Caire Castro-Faria-Neto
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC/Fiocruz), Rio de Janeiro CEP 21040900, Brazil; INCT-NIM - Instituto Oswaldo Cruz-FIOCRUZ, Manguinhos, RJ CEP:21040-360, Brazil
| | - Elizabeth Giestal-de-Araujo
- Programa de Pós-Graduação em Neurociências, Universidade Federal Fluminense, Rio de Janeiro, Brazil; Departamento de Neurobiologia, Laboratório de Cultura de Tecidos Hertha Meyer, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro CEP: 24020-140, Brazil; INCT-NIM - Instituto Oswaldo Cruz-FIOCRUZ, Manguinhos, RJ CEP:21040-360, Brazil
| | - Aline Araujo Dos Santos
- Programa de Pós-Graduação em Neurociências, Universidade Federal Fluminense, Rio de Janeiro, Brazil; Departamento de Fisiologia e Farmacologia, Laboratório de Interações Neuroquímicas e Laboratório de Farmacologia Molecular, Instituto Biomédico, Universidade Federal Fluminense, Niterói, Rio de Janeiro CEP: 24020-150, Brazil.
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Bugueno IM, Benkirane-Jessel N, Huck O. Implication of Toll/IL-1 receptor domain containing adapters in Porphyromonas gingivalis-induced inflammation. Innate Immun 2021; 27:324-342. [PMID: 34018827 PMCID: PMC8186158 DOI: 10.1177/17534259211013087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Periodontitis is induced by periodontal dysbiosis characterized by the predominance of anaerobic species. TLRs constitute the classical pathway for cell activation by infection. Interestingly, the Toll/IL-1 receptor homology domain adapters initiate signaling events, leading to the activation of the expression of the genes involved in the host immune response. The aim of this study was to evaluate the effects of Porphyromonas gingivalis on the expression and protein-protein interactions among five TIR adapters (MAL, MyD88, TRIF, TRAM and SARM) in gingival epithelial cells and endothelial cells. It was observed that P. gingivalis is able to modulate the signaling cascades activated through its recognition by TLR4/2 in gingival epithelial cells and endothelial cells. Indeed, MAL-MyD88 protein-protein interactions associated with TLR4 was the main pathway activated by P. gingivalis infection. When transient siRNA inhibition was performed, cell viability, inflammation, and cell death induced by infection decreased and such deleterious effects were almost absent when MAL or TRAM were targeted. This study emphasizes the role of such TIR adapter proteins in P. gingivalis elicited inflammation and the precise evaluation of TIR adapter protein interactions may pave the way for future therapeutics in both periodontitis and systemic disease with a P. gingivalis involvement, such as atherothrombosis.
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Affiliation(s)
- Isaac M Bugueno
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Nadia Benkirane-Jessel
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Olivier Huck
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.,Faculté de Chirurgie Dentaire, Université de Strasbourg, France.,Pôle de Médecine et de Chirurgie Bucco-Dentaires, Hôpitaux Universitaires de Strasbourg, France
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