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Sanati M, Pieterman I, Levy N, Akbari T, Tavakoli M, Hassani Najafabadi A, Amin Yavari S. Osteoimmunomodulation by bone implant materials: harnessing physicochemical properties and chemical composition. Biomater Sci 2025; 13:2836-2870. [PMID: 40289736 DOI: 10.1039/d5bm00357a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Chronic inflammation at bone defect sites can impede regenerative processes, but local immune responses can be adjusted to promote healing. Regulating the osteoimmune microenvironment, particularly through macrophage polarization, has become a key focus in bone regeneration research. While bone implants are crucial for addressing significant bone defects, they are often recognized by the immune system as foreign, triggering inflammation that leads to bone resorption and implant issues like fibrous encapsulation and aseptic loosening. Developing osteoimmunomodulatory implants offers a promising approach to transforming destructive inflammation into healing processes, enhancing implant integration and bone regeneration. This review explores strategies based on tuning the physicochemical attributes and chemical composition of materials in engineering osteoimmunomodulatory and pro-regenerative bone implants.
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Affiliation(s)
- Mehdi Sanati
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Ines Pieterman
- Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Natacha Levy
- Metabolic Diseases Pediatrics Division, University Medical Centre Utrecht, Utrecht, The Netherlands
- Regenerative Medicine Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Tayebeh Akbari
- Department of Microbiology, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Mohamadreza Tavakoli
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Saber Amin Yavari
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands.
- Regenerative Medicine Centre Utrecht, Utrecht University, Utrecht, The Netherlands
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2
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Ge Z, Wu Q, Lv C, He Q. The Roles of T Cells in the Development of Metabolic Dysfunction-Associated Steatohepatitis. Immunology 2025. [PMID: 40414629 DOI: 10.1111/imm.13943] [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: 12/04/2024] [Revised: 02/28/2025] [Accepted: 04/28/2025] [Indexed: 05/27/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.
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Affiliation(s)
- Zhifa Ge
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qingwei Wu
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chengyu Lv
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qifeng He
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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3
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Roman-Pepine D, Serban AM, Capras RD, Cismaru CM, Filip AG. A Comprehensive Review: Unraveling the Role of Inflammation in the Etiology of Heart Failure. Heart Fail Rev 2025:10.1007/s10741-025-10519-w. [PMID: 40360833 DOI: 10.1007/s10741-025-10519-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2025] [Indexed: 05/15/2025]
Abstract
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. This comprehensive review aims to elucidate the intricate mechanisms by which inflammation contributes to the development and progression of HF. The review synthesizes current research on the involvement of both innate and adaptive immune responses in HF, highlighting the roles of cytokines, chemokines, and other inflammatory mediators. Recent studies have demonstrated that chronic inflammation, driven by factors such as oxidative stress, neurohormonal activation, and metabolic disturbances, leads to adverse cardiac remodeling and impaired myocardial function. The review explores how systemic inflammation, characterized by elevated levels of inflammatory biomarkers like C-reactive protein (CRP) and interleukin-6 (IL-6), correlates with HF severity and outcomes. Additionally, it discusses the impact of comorbid conditions such as diabetes, obesity, and hypertension on inflammatory pathways and HF risk. The review also delves into the therapeutic implications of targeting inflammation in HF. Despite mixed results from early clinical trials, emerging evidence suggests that anti-inflammatory therapies offer benefits in specific HF phenotypes. The potential of novel therapeutic strategies, including the use of biologics and small molecule inhibitors, is examined in the context of their ability to modulate inflammatory responses and improve clinical outcomes.
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Affiliation(s)
- Diana Roman-Pepine
- Department of Anatomy and Embryology, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania.
- Cardiology Department, Heart Institute Niculae Stăncioiu, 19-21 Motilor Street, 400001, Cluj-Napoca- Napoca, Romania.
| | - Adela Mihaela Serban
- Cardiology Department, Heart Institute Niculae Stăncioiu, 19-21 Motilor Street, 400001, Cluj-Napoca- Napoca, Romania
- 5 Th Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
| | - Roxana-Denisa Capras
- Department of Anatomy and Embryology, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
| | - Cristina Mihaela Cismaru
- Department of Infectious Diseases, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
| | - Adriana Gabriela Filip
- Department of Anatomy and Embryology, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
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Sadeghi M, Moghaddam A, Amiri AM, Charoghdoozi K, Mohammadi M, Dehnavi S, Orazizadeh M. Improving the Wound Healing Process: Pivotal role of Mesenchymal stromal/stem Cells and Immune Cells. Stem Cell Rev Rep 2025; 21:680-697. [PMID: 39921839 DOI: 10.1007/s12015-025-10849-0] [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] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
Wound healing, a physiological process, involves several different types of cells, from immune cells to non-immune cells, including mesenchymal stromal/stem cells (MSC), and their interactions. Immune cells including macrophages, neutrophils, dendritic cells (DC), innate lymphoid cells (ILC), natural killer (NK) cells, and B and T lymphocytes participate in wound healing by secreting various mediators and interacting with other cells. MSCs, as self-renewing, fast proliferating, and multipotent stromal/stem cells, are found in a wide variety of tissues and critically involved in different phases of wound healing by secreting various molecules that help to improve tissue healing and regeneration. In this review, first, we described the four main phases of wound healing, second, we reviewed the function of MSCs, MSC secretome and immune cells in improving the progress of wound repair (mainly focusing on skin wound healing), third, we explained the immune cells/MSCs interactions in the process of wound healing and regeneration, and finally, we introduce clinical applications of MSCs to improve the process of wound healing.
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Affiliation(s)
- Mahvash Sadeghi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Moghaddam
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Mohammad Amiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kianush Charoghdoozi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojgan Mohammadi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Dehnavi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Orazizadeh
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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5
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Shimizu T, Abe S, Kawaguchi Y, Takata H, Ando H, Ishida T. A spleen-targeted vaccine for SARS-CoV-2 - Inducting neutralizing antibodies in mice. J Pharm Sci 2025; 114:1615-1624. [PMID: 39892872 DOI: 10.1016/j.xphs.2025.01.024] [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] [Received: 10/27/2024] [Revised: 01/25/2025] [Accepted: 01/25/2025] [Indexed: 02/04/2025]
Abstract
The development of vaccines against infectious diseases is of the utmost importance to prevent global pandemics such as COVID-19. The application of antigens and adjuvants to efficiently target antigen presenting cells (APCs) is paramount for the development of efficient vaccines. In our previous study, we showed that splenic marginal zone-B (MZ-B) cells are promising APCs in addition to dendritic cells (DCs). In this study we achieved the targeted delivery of sufficient antigen to MZ-B cells by utilizing an intravenous (IV) immunization system we originally developed. This system involves the sequential injection of empty PEGylated liposomes (PEG-Lip) and antigen-containing PEG-Lip within a prescribed interval. Herein, we describe the application of this IV immunization system as a COVID-19 vaccine to induce specific antibodies against SARS-CoV-2. To establish efficacy, SARS-CoV-2 spike proteins were used as an antigen, and α-galactosylceramide (GC) was used as an adjuvant in this study. Three days after priming with empty PEG-Lip, we injected PEG-Lip containing spike protein and α-GC. Our IV immunization system successfully induced higher levels of anti-spike antibodies when spike protein derived from HEK-293, but not E. coli., was injected into mice. The levels were less produced using conventional immunization via subcutaneous (s.c.) injections of complete Freund's adjuvant without priming. Interestingly, a lower dose (0.2 µg) of spike protein antigen encapsulated into PEG-Lip induced a higher level of anti-spike antibodies than that produced using a significantly higher dose (5 µg). The induced anti-spike antibodies inhibited the interaction between the receptor binding domain of the spike protein and the angiotensin-converting enzyme 2. This indicates that the induced antibodies tend to neutralize SARS-CoV-2. Collectively, the specific delivery of spike proteins to spleen, probably MZ-B cells, via nano-carriers could be a promising approach for the development of global pandemic vaccines that require only minimum dosages of antigen.
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Affiliation(s)
- Taro Shimizu
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan.
| | - Shunji Abe
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan
| | - Yoshino Kawaguchi
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan
| | - Haruka Takata
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan; Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, 770-8505, Tokushima, Japan
| | - Hidenori Ando
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan; Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, 770-8505, Tokushima, Japan
| | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, 770-8505, Japan; Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, 770-8505, Tokushima, Japan.
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6
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Xie GL, Zhong ZH, Ye TW, Xiao ZQ. Radiofrequency ablation combined with immunotherapy to treat hepatocellular carcinoma: a comprehensive review. BMC Surg 2025; 25:47. [PMID: 39875933 PMCID: PMC11776151 DOI: 10.1186/s12893-025-02778-z] [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: 03/27/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is a highly immunogenic tumor and the third leading cause of cancer-related deaths worldwide with an increasing incidence. Therefore, the combination of immunotherapy with other approaches, such as anti-angiogenic agents and local area therapy, has become a new strategy for HCC treatment. METHODS We searched PubMed and Web of Science and extracted publications relating to the radiofrequency ablation (RFA) and immunotherapy. The search terms were: "radiofrequency ablation", "immunotherapy" and "hepatocellular carcinoma", and manual searches of eligible articles from literature reference lists were performed. We then thoroughly reviewed the literature on ablation combined with immunotherapy for HCC, analyzed the relevant mechanism, and explored the safety and effectiveness of this form of combination therapy. RESULTS RFA combined with immunotherapy in HCC is reported to have good efficacy and controllable safety. On the one hand, RFA can induce the immunogenic substances including Ficolin-3, IL-1 and heat shock protein and regulate the immune cells by mediating the Th1/Th2 ratio, increasing Th17 cells, etc. On the other hand, RFA treatment can lead to tumor immune microenvironment reconstruction, increasing the proportion of functional T cells and upregulate PD-1 in T cells in distant tumors without RFA. This combined strategy has the ability to enhance the anti-tumor immune response through synergies, significantly reduce the risk of recurrence and improve survival. CONCLUSIONS RFA combined with immunotherapy yields a good synergistic effect: it can further strengthen anti-tumor response, delay distant tumor growth, reduce tumor recurrence and metastasis, providing new options for HCC systemic treatment.
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Affiliation(s)
- Gui-Lin Xie
- Department of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Zhi-Han Zhong
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Tai-Wei Ye
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Zun-Qiang Xiao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
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7
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Guo Z, Yao Z, Huang B, Wu D, Li Y, Chen X, Lu Y, Wang L, Lv W. MAFLD-related hepatocellular carcinoma: Exploring the potent combination of immunotherapy and molecular targeted therapy. Int Immunopharmacol 2024; 140:112821. [PMID: 39088919 DOI: 10.1016/j.intimp.2024.112821] [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] [Received: 05/23/2024] [Revised: 07/11/2024] [Accepted: 07/25/2024] [Indexed: 08/03/2024]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity globally, and with the prevalence of metabolic-related diseases, the incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) related hepatocellular carcinoma (MAFLD-HCC) continues to rise with the limited efficacy of conventional treatments, which has created a major challenge for HCC surveillance. Immune checkpoint inhibitors (ICIs) and molecularly targeted drugs offer new hope for advanced MAFLD-HCC, but the evidence for the use of both types of therapy in this type of tumour is still insufficient. Theoretically, the combination of immunotherapy, which awakens the body's anti-tumour immunity, and targeted therapies, which directly block key molecular events driving malignant progression in HCC, is expected to produce synergistic effects. In this review, we will discuss the progress of immunotherapy and molecular targeted therapy in MAFLD-HCC and look forward to the opportunities and challenges of the combination therapy.
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Affiliation(s)
- Ziwei Guo
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ziang Yao
- Department of Traditional Chinese Medicine, Peking University People 's Hospital, Beijing 100044, China
| | - Bohao Huang
- Beijing University of Chinese Medicine, Beijing 100105, China
| | - Dongjie Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Yanbo Li
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xiaohan Chen
- Department of Hematology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yanping Lu
- Department of Hepatology, Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518100, China.
| | - Li Wang
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Wenliang Lv
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Song D, Heo JW, Kim JS, Jung J, Jang HH, Hwang IG, Shim CK, Ham JS, Park SY, Lee SH. Anti-obesity and immunomodulatory effects of Allium hookeri leaves cultivated with artificial light of different intensities on immune-depressed obese mice. Biomed Pharmacother 2024; 179:117393. [PMID: 39260326 DOI: 10.1016/j.biopha.2024.117393] [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] [Received: 05/31/2024] [Revised: 08/20/2024] [Accepted: 08/30/2024] [Indexed: 09/13/2024] Open
Abstract
This study was conducted to evaluate the effects of Allium hookeri (AH) leaves cultivated with different light-emitting diode (LED) intensities (L: low, 100 μmol/m2/s; M: medium, 150 μmol/m2/s; H: high, 200 μmol/m2/s). Alliin concentration increased as light intensity increased in AH and showed the highest level at LED-H condition. The anti-obesity and immunomodulatory properties of AH were evaluated in a cyclophosphamide (CPA)-induced immunosuppressed obese animal model. C57BL/6 J mice were randomly divided into control (CON), high-fat diet (HFD) control (CON-H), negative control (NC), positive control (PC, β-glucan, 50 mg/kg body weight (BW)), AH L, M, and H groups. The three kinds of AH extracts were orally administered to the mice at 300 mg/kg BW for 2 weeks. Except for CON and CON-H, all the other groups were intraperitoneally treated with CPA. Epididymal and abdominal fat weight decreased as LED intensity increased while spleen weight increased in the AH groups. Serum glucose decreased as LED intensity increased in the AH groups and H group showed the lowest level. Triglycerides, total, and LDL-cholesterol levels decreased while HDL-cholesterol level increased in the AH groups compared to the NC group. Moreover, AH effectively reduced serum ALT and AST levels and increased the total white blood cell count, particularly elevating lymphocyte and monocyte levels. Furthermore, NK cell activity was higher in the AH groups. These findings suggest that AH cultivated at optimal LED intensity could be used as a novel biomedicine and in pharmacotherapy to treat related diseases to improve public health without any toxicity.
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Affiliation(s)
- Doyoung Song
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Jeong-Wook Heo
- Department of Agricultural Engineering, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Ji-Su Kim
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Jieun Jung
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Hwan-Hee Jang
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - In-Guk Hwang
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Chang-Ki Shim
- Department of Agricultural Environment, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea; Division of Planning and Coordination, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Jun Sang Ham
- Department of Animal Biotechnology and Environment, National Institute of Animal Science, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Shin-Young Park
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea
| | - Sung-Hyen Lee
- Department of Agro-Food Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Republic of Korea.
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Zhu J, Jin A, Pan B, Guo W, Yang W, Wang B. Exploring the role of KIR3DL2 on NK cells in hepatocellular carcinoma and its potential prognostic implications. iScience 2024; 27:110637. [PMID: 39262781 PMCID: PMC11388180 DOI: 10.1016/j.isci.2024.110637] [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: 02/27/2024] [Revised: 07/10/2024] [Accepted: 07/30/2024] [Indexed: 09/13/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a globally prevalent malignancy with a high recurrence rate, significantly impacting prognosis and survival. This study aims to identify prognostic molecular markers using single-cell sequencing of tumors and adjacent tissues in primary and recurrent HCC patients. We analyzed single-cell sequencing data from tumor and adjacent normal tissues of primary and recurrent HCC cases to compare immune cell quantity and gene expression profiles. Recurrent HCC patients exhibited a significant reduction in infiltrating NK cells expressing KIR3DL2. Pseudotemporal and cell communication analyses revealed these KIR3DL2high NK cells were in a quiescent state, suggesting NK cell exhaustion and poor prognosis. KIR3DL2 expression in peripheral blood NK cells correlated with that in tissues, highlighting its potential as a prognostic marker for HCC.
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Affiliation(s)
- Jie Zhu
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Anli Jin
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Baishen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Laboratory Medicine, Shanghai Geriatric Medical Center, Zhongshan Hospital, Fudan University, Shanghai 201104, China
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen 361015, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai 200940, China
| | - Wenjing Yang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Beili Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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10
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Hmiel L, Zhang S, Obare LM, Santana MADO, Wanjalla CN, Titanji BK, Hileman CO, Bagchi S. Inflammatory and Immune Mechanisms for Atherosclerotic Cardiovascular Disease in HIV. Int J Mol Sci 2024; 25:7266. [PMID: 39000373 PMCID: PMC11242562 DOI: 10.3390/ijms25137266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH.
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Affiliation(s)
- Laura Hmiel
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center and Case Western Reserve University, Cleveland, OH 44109, USA
| | - Suyu Zhang
- Department of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Laventa M. Obare
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | | | - Celestine N. Wanjalla
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Boghuma K. Titanji
- Division of Infectious Diseases, Emory University, Atlanta, GA 30322, USA
| | - Corrilynn O. Hileman
- Department of Medicine, Division of Infectious Disease, MetroHealth Medical Center and Case Western Reserve University, Cleveland, OH 44109, USA
| | - Shashwatee Bagchi
- Division of Infectious Diseases, Washington University in St. Louis, St. Louis, MO 63110, USA
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11
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Hsu CY, Mustafa MA, Kumar A, Pramanik A, Sharma R, Mohammed F, Jawad IA, Mohammed IJ, Alshahrani MY, Ali Khalil NAM, Shnishil AT, Abosaoda MK. Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles. Pathol Res Pract 2024; 256:155266. [PMID: 38554489 DOI: 10.1016/j.prp.2024.155266] [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: 02/20/2024] [Revised: 03/05/2024] [Accepted: 03/15/2024] [Indexed: 04/01/2024]
Abstract
Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan
| | | | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Atreyi Pramanik
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Rajiv Sharma
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Faraj Mohammed
- Department of Pharmacy, Al-Manara College for Medical Sciences, Maysan, Iraq
| | | | - Imad Jasim Mohammed
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | | | | | - Munther Kadhim Abosaoda
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Iraq
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12
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Nie J, Ai J, Hong W, Bai Z, Wang B, Yang J, Zhang Z, Mo F, Yang J, Sun Q, Wei X. Cisplatin-induced oxPAPC release enhances MDSCs infiltration into LL2 tumour tissues through MCP-1/CCL2 and LTB4/LTB4R pathways. Cell Prolif 2024; 57:e13570. [PMID: 37905494 PMCID: PMC10984104 DOI: 10.1111/cpr.13570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/09/2023] [Accepted: 10/15/2023] [Indexed: 11/02/2023] Open
Abstract
Lung cancer is the leading global cause of cancer-related death, however, resistance to chemotherapy drugs remains a huge barrier to effective treatment. The elevated recruitment of myeloid derived suppressor cells (MDSCs) to tumour after chemotherapy has been linked to resistance of chemotherapy drugs. Nevertheless, the specific mechanism remains unclear. oxPAPC is a bioactive principal component of minimally modified low-density lipoproteins and regulates inflammatory response. In this work, we found that cisplatin, oxaliplatin and ADM all increased oxPAPC release in tumour. Treating macrophages with oxPAPC in vitro stimulated the secretion of MCP-1 and LTB4, which strongly induced monocytes and neutrophils chemotaxis, respectively. Injection of oxPAPC in vivo significantly upregulated the percentage of MDSCs in tumour microenvironment (TME) of wild-type LL2 tumour-bearing mice, but not CCL2-/- mice and LTB4R-/- mice. Critically, oxPAPC acted as a pro-tumor factor in LL2 tumour model. Indeed, cisplatin increased oxPAPC level in tumour tissues of WT mice, CCL2-/- and LTB4R-/- mice, but caused increased infiltration of Ly6Chigh monocytes and neutrophils only in WT LL2-bearing mice. Collectively, our work demonstrates cisplatin treatment induces an overproduction of oxPAPC and thus recruits MDSCs infiltration to promote the tumour growth through the MCP-1/CCL2 and LTB4/LTB4R pathways, which may restrict the effect of multiple chemotherapy. This provides evidence for a potential strategy to enhance the efficacy of multiple chemotherapeutic drugs in the treatment of lung cancer by targeting oxPAPC.
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Affiliation(s)
- Ji Nie
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan ProvinceThe Affiliated Hospital of Kunming University of Science and TechnologyKunmingYunnanChina
| | - Jiayuan Ai
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Weiqi Hong
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ziyi Bai
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Binhan Wang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Jingyun Yang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ziqi Zhang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Fei Mo
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Jing Yang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Qiu Sun
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
- West China Medical Publishers, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xiawei Wei
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
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13
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Hoque MM, Gbadegoye JO, Hassan FO, Raafat A, Lebeche D. Cardiac fibrogenesis: an immuno-metabolic perspective. Front Physiol 2024; 15:1336551. [PMID: 38577624 PMCID: PMC10993884 DOI: 10.3389/fphys.2024.1336551] [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: 11/16/2023] [Accepted: 03/07/2024] [Indexed: 04/06/2024] Open
Abstract
Cardiac fibrosis is a major and complex pathophysiological process that ultimately culminates in cardiac dysfunction and heart failure. This phenomenon includes not only the replacement of the damaged tissue by a fibrotic scar produced by activated fibroblasts/myofibroblasts but also a spatiotemporal alteration of the structural, biochemical, and biomechanical parameters in the ventricular wall, eliciting a reactive remodeling process. Though mechanical stress, post-infarct homeostatic imbalances, and neurohormonal activation are classically attributed to cardiac fibrosis, emerging evidence that supports the roles of immune system modulation, inflammation, and metabolic dysregulation in the initiation and progression of cardiac fibrogenesis has been reported. Adaptive changes, immune cell phenoconversions, and metabolic shifts in the cardiac nonmyocyte population provide initial protection, but persistent altered metabolic demand eventually contributes to adverse remodeling of the heart. Altered energy metabolism, mitochondrial dysfunction, various immune cells, immune mediators, and cross-talks between the immune cells and cardiomyocytes play crucial roles in orchestrating the transdifferentiation of fibroblasts and ensuing fibrotic remodeling of the heart. Manipulation of the metabolic plasticity, fibroblast-myofibroblast transition, and modulation of the immune response may hold promise for favorably modulating the fibrotic response following different cardiovascular pathological processes. Although the immunologic and metabolic perspectives of fibrosis in the heart are being reported in the literature, they lack a comprehensive sketch bridging these two arenas and illustrating the synchrony between them. This review aims to provide a comprehensive overview of the intricate relationship between different cardiac immune cells and metabolic pathways as well as summarizes the current understanding of the involvement of immune-metabolic pathways in cardiac fibrosis and attempts to identify some of the previously unaddressed questions that require further investigation. Moreover, the potential therapeutic strategies and emerging pharmacological interventions, including immune and metabolic modulators, that show promise in preventing or attenuating cardiac fibrosis and restoring cardiac function will be discussed.
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Affiliation(s)
- Md Monirul Hoque
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Joy Olaoluwa Gbadegoye
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Fasilat Oluwakemi Hassan
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Amr Raafat
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Djamel Lebeche
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
- Medicine-Cardiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
- Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
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14
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Ji YZ, Jia LL, Liu SR. Inflammation and epigenetics of sporotrichosis disease. Semin Cell Dev Biol 2024; 154:193-198. [PMID: 36990829 DOI: 10.1016/j.semcdb.2023.02.014] [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: 01/23/2023] [Revised: 02/26/2023] [Accepted: 02/26/2023] [Indexed: 03/30/2023]
Abstract
Sporotrichosis, a fungal disease, is caused by exposure to soil that harbors Sporothrix schenckii or through inhalation of fungal spores. Skin is the most frequently exposed organ making sporotrichosis a primarily dermal disease. Many described reports in the literature suggest a connection of sporotrichosis with cutaneous squamous cell carcinoma with some connection between initial sporotrichosis diagnosis and treatment followed by development of cutaneous squamous cell carcinoma at the very site. Conversely, there is also evidence for sporotrichosis subsequent to skin cancer diagnosis, even after cancer chemotherapy, which points towards weakening of immune response by cancer chemotherapy leading to attack and infection by Sporothrix schenckii. We also propose and focus on inflammation as the connection between sporotrichosis, cancer and even the metastatic spread of cancer. Inflammation-associated IL-6, IFN-γ, natural killer cells and M2-macrophages possibly mechanistically link sporotrichosis with cancer, particularly cutaneous squamous cell carcinoma. These inflammation related factors/cells are regulated epigenetically raising the possibility of epigenetic regulation of sporotrichosis, which has not been described yet in the available literature. Clinical management of inflammation may thus be effective strategy not just against sporotrichosis but also the related onset of cutaneous squamous cell carcinoma and possibly its metastasis to lymph nodes.
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Affiliation(s)
- Yong-Zhi Ji
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, China
| | - Li-Li Jia
- Department of Dermatology, FAW General Hospital, Changchun, China
| | - Shi-Rui Liu
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, China.
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15
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Rodriguez-Mogeda C, van Ansenwoude CMJ, van der Molen L, Strijbis EMM, Mebius RE, de Vries HE. The role of CD56 bright NK cells in neurodegenerative disorders. J Neuroinflammation 2024; 21:48. [PMID: 38350967 PMCID: PMC10865604 DOI: 10.1186/s12974-024-03040-8] [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: 11/10/2023] [Accepted: 02/07/2024] [Indexed: 02/15/2024] Open
Abstract
Emerging evidence suggests a potential role for natural killer (NK) cells in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise function of NK cells in these diseases remains ambiguous. The existence of two NK cell subsets, CD56bright and CD56dim NK cells, complicates the understanding of the contribution of NK cells in neurodegeneration as their functions within the context of neurodegenerative diseases may differ significantly. CD56bright NK cells are potent cytokine secretors and are considered more immunoregulatory and less terminally differentiated than their mostly cytotoxic CD56dim counterparts. Hence, this review focusses on NK cells, specifically on CD56bright NK cells, and their role in neurodegenerative diseases. Moreover, it explores the mechanisms underlying their ability to enter the central nervous system. By consolidating current knowledge, we aim to provide a comprehensive overview on the role of CD56bright NK cells in neurodegenerative diseases. Elucidating their impact on neurodegeneration may have implications for future therapeutic interventions, potentially ameliorating disease pathogenesis.
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Affiliation(s)
- Carla Rodriguez-Mogeda
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Neuroscience, Amsterdam, The Netherlands
- MS Center Amsterdam, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands
| | - Chaja M J van Ansenwoude
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Neuroscience, Amsterdam, The Netherlands
- MS Center Amsterdam, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands
| | - Lennart van der Molen
- IQ Health Science Department, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eva M M Strijbis
- Amsterdam Neuroscience, Amsterdam, The Netherlands
- MS Center Amsterdam, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands
- Department of Neurology, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands
| | - Reina E Mebius
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Infection and Immunity Institute, Amsterdam, The Netherlands
| | - Helga E de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Neuroscience, Amsterdam, The Netherlands.
- MS Center Amsterdam, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands.
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16
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Bourinet M, Anty R, Gual P, Luci C. Roles of innate lymphoid cells in metabolic and alcohol-associated liver diseases. JHEP Rep 2024; 6:100962. [PMID: 38304237 PMCID: PMC10831956 DOI: 10.1016/j.jhepr.2023.100962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/09/2023] [Accepted: 10/25/2023] [Indexed: 02/03/2024] Open
Abstract
Innate lymphoid cells (ILCs) have been identified as potent regulators of inflammation, cell death and wound healing, which are the main biological processes involved in the progression of chronic liver disease. Obesity and chronic alcohol consumption are the leading contributors to chronic liver diseases in developed countries, due to inappropriate lifestyles. In particular, inflammation is a key factor in these liver abnormalities and promotes the development of more severe lesions such as fibrosis, cirrhosis and hepatocellular carcinoma. Opposite roles of ILC subsets have been described in the development of chronic liver disease, depending on the stage and aetiology of the disease. The heterogeneous family of ILCs encompasses cytotoxic natural killer cells, the cytokine-producing type 1, 2 and 3 ILCs and lymphoid tissue inducer cells. Dysfunction of these immune cells provokes uncontrolled inflammation and tissue damage, which are the basis for tumour development. In this review, we provide an overview of the recent and putative roles of ILC subsets in obesity and alcohol-associated liver diseases, which are currently the major contributors to end-stage liver complications such as fibrosis/cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Manon Bourinet
- Université Côte d’Azur, INSERM, U1065, C3M, Nice, France
| | - Rodolphe Anty
- Université Côte d’Azur, CHU, INSERM, U1065, C3M, Nice, France
| | - Philippe Gual
- Université Côte d’Azur, INSERM, U1065, C3M, Nice, France
| | - Carmelo Luci
- Université Côte d’Azur, INSERM, U1065, C3M, Nice, France
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17
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Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med 2024; 95:101231. [PMID: 38056058 DOI: 10.1016/j.mam.2023.101231] [Citation(s) in RCA: 53] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/13/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023]
Abstract
Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.
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Affiliation(s)
- Maurizio Parola
- Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine - Royal Free Hospital, London, NW32PF, United Kingdom.
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18
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Yang Y, Zhang C, Jiang Y, He Y, Cai J, Liang L, Chen Z, Pan S, Hua C, Wu K, Wang L, Zhang Z. Harnessing cytokine-induced killer cells to accelerate diabetic wound healing: an approach to regulating post-traumatic inflammation. Regen Biomater 2024; 11:rbad116. [PMID: 38333727 PMCID: PMC10850840 DOI: 10.1093/rb/rbad116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 02/10/2024] Open
Abstract
Impaired immunohomeostasis in diabetic wounds prolongs inflammation and cytokine dysfunction, thus, delaying or preventing wound-surface healing. Extensive clinical studies have been conducted on cytokine-induced killer (CIK) cells recently, as they can be easily proliferated using a straightforward, inexpensive protocol. Therefore, the function of CIK cells in regulating inflammatory environments has been drawing attention for clinical management. Throughout the current investigation, we discovered the regenerative capacity of these cells in the challenging environment of wounds that heal poorly due to diabetes. We demonstrated that the intravenous injection of CIK cells can re-establish a proregenerative inflammatory microenvironment, promote vascularization and, ultimately, accelerate skin healing in diabetic mice. The results indicated that CIK cell treatment affects macrophage polarization and restores the function of regenerative cells under hyperglycemic conditions. This novel cellular therapy offers a promising intervention for clinical applications through specific inflammatory regulation functions.
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Affiliation(s)
- Yixi Yang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Cheng Zhang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Yuan Jiang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Yijun He
- Department of Osteoarthropathy and Sports Medicine, Panyu Central Hospital, Guangzhou 511400, P. R. China
| | - Jiawei Cai
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Lin Liang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Zhaohuan Chen
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Sicheng Pan
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Chu Hua
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Keke Wu
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Le Wang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
| | - Zhiyong Zhang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, Department of Orthopaedic Surgery, Medical Technology and Related Equipment Research for Spinal Injury Treatment, City Key Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong 510150, P. R. China
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19
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Huang J, Wu Q, Geller DA, Yan Y. Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC). J Transl Med 2023; 21:815. [PMID: 37968714 PMCID: PMC10652641 DOI: 10.1186/s12967-023-04716-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/09/2023] [Indexed: 11/17/2023] Open
Abstract
The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.
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Affiliation(s)
- Jingquan Huang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China
| | - Qiulin Wu
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China
| | - David A Geller
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
| | - Yihe Yan
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China.
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20
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Abdelrahman BA, El-Khatib AS, Attia YM. Insights into the role of vitamin D in targeting the culprits of non-alcoholic fatty liver disease. Life Sci 2023; 332:122124. [PMID: 37742738 DOI: 10.1016/j.lfs.2023.122124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Vitamin D (VD) is a secosteroid hormone that is renowned for its crucial role in phospho-calcium homeostasis upon binding to the nuclear vitamin D receptor (VDR). Over and above, the pleiotropic immunomodulatory, anti-inflammatory, and metabolic roles VD plays in different disease settings started to surface in the past few decades. On the other hand, a growing body of evidence suggests a correlation between non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) with vitamin D deficiency (VDD) owing to the former's ingrained link with obesity and metabolic syndrome. Accordingly, a better understanding of the contribution of disrupted VDR signalling to NAFLD incidence and progression would provide further insights into its diagnosis, treatment modalities, and prognosis. This is especially significant as, hitherto, no drug for NAFLD has been approved. This review, therefore, sought to set forth the likely contribution of VDR signalling in NAFLD and how it might influence its multiple drivers.
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Affiliation(s)
- Basma A Abdelrahman
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Yasmeen M Attia
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
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21
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Shabrish S, Chandrakasan S, Madkaikar M. Editorial: NK cell defects: diagnosis and treatment. Front Immunol 2023; 14:1323793. [PMID: 38022628 PMCID: PMC10644773 DOI: 10.3389/fimmu.2023.1323793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Affiliation(s)
- Snehal Shabrish
- Translational Research Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Shanmuganathan Chandrakasan
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, United States
| | - Manisha Madkaikar
- Department of Pediatric Immunology & Leukocyte Biology, Indian Council of Medical Research - National Institute of Immunohaematology, King Edward Memorial (KEM) Hospital, Mumbai, Maharashtra, India
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22
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Khan MA, Lau CL, Krupnick AS. Monitoring regulatory T cells as a prognostic marker in lung transplantation. Front Immunol 2023; 14:1235889. [PMID: 37818354 PMCID: PMC10561299 DOI: 10.3389/fimmu.2023.1235889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/11/2023] [Indexed: 10/12/2023] Open
Abstract
Lung transplantation is the major surgical procedure, which restores normal lung functioning and provides years of life for patients suffering from major lung diseases. Lung transplant recipients are at high risk of primary graft dysfunction, and chronic lung allograft dysfunction (CLAD) in the form of bronchiolitis obliterative syndrome (BOS). Regulatory T cell (Treg) suppresses effector cells and clinical studies have demonstrated that Treg levels are altered in transplanted lung during BOS progression as compared to normal lung. Here, we discuss levels of Tregs/FOXP3 gene expression as a crucial prognostic biomarker of lung functions during CLAD progression in clinical lung transplant recipients. The review will also discuss Treg mediated immune tolerance, tissue repair, and therapeutic strategies for achieving in-vivo Treg expansion, which will be a potential therapeutic option to reduce inflammation-mediated graft injuries, taper the toxic side effects of ongoing immunosuppressants, and improve lung transplant survival rates.
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Myo Oo TZ, Saichua P, Phoksawat W, Sithithaworn P, Mairiang E, Sripa B, Leelayuwat C, Jumnainsong A. Association of MICA Gene Polymorphism in Opisthorchis viverrini-Induced Periductal Fibrosis in Northeastern Thais. Asian Pac J Cancer Prev 2023; 24:3213-3219. [PMID: 37774074 PMCID: PMC10762729 DOI: 10.31557/apjcp.2023.24.9.3213] [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] [Received: 05/21/2023] [Accepted: 09/10/2023] [Indexed: 10/01/2023] Open
Abstract
OBJECTIVE Chronic Opisthorchis viverrini (OV) infection is the cause of advanced periductal fibrosis (APF), subsequently leading to cholangiocarcinoma (CCA). Natural killer (NK) cells can kill hepatic stellate cells (HSCs), the initiating cells for fibrosis formation, by using the interaction between the natural killer group 2 member D (NKG2D) receptor and its ligand on the HSCs. This can inhibit the fibrosis formation. Major histocompatibility complex class I chain-related A (MICA) is the ligand of the NKG2D receptor and has highly polymorphic characteristics that are involved in NKG2D binding and NK cell activation. This study aimed to investigate the polymorphism of MICA in OV-induced fibrosis. METHOD MICA typing was performed by polymerase chain reaction- sequence specific primer (PCR-SSP) and sequencing in two groups: OV infection without fibrosis (N = 99) and with fibrosis (N = 290). RESULT Six alleles were identified and the MICA*010 allele had the highest frequency in both groups. The MICA*00201-02 allele was a protective factor for fibrosis (OR= 0.508, 95%CI= 0.34-0.76, Pc <0.05), while the MICA*019 allele was suggested to be a risk allele for fibrosis (OR=1.95, 95%CI=1.25-3.03, Pc<0.005). In addition, two motifs, glycine (G) at position 14 and glutamine (Q) at position 251, were negatively associated with fibrosis (G14: OR=0.508, 95%CI=0.34-0.76, Pc <0.05 and Q251: OR=0.586, 95%CI=0.41-0.84, Pc <0.05). Moreover, the distribution of the MICA-129 genotype also showed the protective genotype (Pc<0.05, OR=0.319, 95%CI= 0.12-0.54) for fibrosis. The MICA*00201-02 allele encoded all these motifs, and this suggested that it might lead to strong NK cell activation to kill HSCs, subsequently preventing fibrosis formation. CONCLUSION This study described initial evidence suggesting that the polymorphism of the MICA gene might be a marker for OV-derived periductal fibrosis.
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Affiliation(s)
- Tay Zar Myo Oo
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
| | - Prasert Saichua
- Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Tropical Disease Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Wisitsak Phoksawat
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Paiboon Sithithaworn
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Eimorn Mairiang
- Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Banchob Sripa
- Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- Tropical Disease Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| | - Chanvit Leelayuwat
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
| | - Amonrat Jumnainsong
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
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24
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He X, Xu R, Pan L, Bhattarai U, Liu X, Zeng H, Chen JX, Hall ME, Chen Y. Inhibition of NK1.1 signaling attenuates pressure overload-induced heart failure, and consequent pulmonary inflammation and remodeling. Front Immunol 2023; 14:1215855. [PMID: 37554327 PMCID: PMC10405176 DOI: 10.3389/fimmu.2023.1215855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 07/05/2023] [Indexed: 08/10/2023] Open
Abstract
Background Inflammation contributes to heart failure (HF) development, the progression from left ventricular failure to pulmonary remodeling, and the consequent right ventricular hypertrophy and failure. NK1.1 plays a critical role in Natural killer (NK) and NK T (NKT) cells, but the role of NK1.1 in HF development and progression is unknown. Methods We studied the effects of NK1.1 inhibition on transverse aortic constriction (TAC)-induced cardiopulmonary inflammation, HF development, and HF progression in immunocompetent male mice of C57BL/6J background. Results We found that NK1.1+ cell-derived interferon gamma+ (IFN-γ+) was significantly increased in pulmonary tissues after HF. In addition, anti-NK1.1 antibodies simultaneously abolished both NK1.1+ cells, including the NK1.1+NK and NK1.1+NKT cells in peripheral blood, spleen, and lung tissues, but had no effect on cardiopulmonary structure and function under control conditions. However, systemic inhibition of NK1.1 signaling by anti-NK1.1 antibodies significantly rescued mice from TAC-induced left ventricular inflammation, fibrosis, and failure. Inhibition of NK1.1 signaling also significantly attenuated TAC-induced pulmonary leukocyte infiltration, fibrosis, vessel remodeling, and consequent right ventricular hypertrophy. Moreover, inhibition of NK1.1 signaling significantly reduced TAC-induced pulmonary macrophage and dendritic cell infiltration and activation. Conclusions Our data suggest that inhibition of NK1.1 signaling is effective in attenuating systolic overload-induced cardiac fibrosis, dysfunction, and consequent pulmonary remodeling in immunocompetent mice through modulating the cardiopulmonary inflammatory response.
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Affiliation(s)
- Xiaochen He
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Rui Xu
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Lihong Pan
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Umesh Bhattarai
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Xiaoguang Liu
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
- College of Sports and Health, Guangzhou Sport University, Guangzhou, China
| | - Heng Zeng
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Jian-Xiong Chen
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Michael E. Hall
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
- Department of Medicine, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
| | - Yingjie Chen
- Department of Physiology and Biophysics, University of Mississippi Medical Center, School of Medicine, Jackson, MS, United States
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25
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Jiang W, Xu Y, Chen JC, Lee YH, Hu Y, Liu CH, Chen E, Tang H, Zhang H, Wu D. Role of extracellular vesicles in nonalcoholic fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1196831. [PMID: 37534206 PMCID: PMC10392952 DOI: 10.3389/fendo.2023.1196831] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/21/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that affects approximately one-quarter of the global population and is becoming increasingly prevalent worldwide. The lack of current noninvasive tools and efficient treatment is recognized as a significant barrier to the clinical management of these conditions. Extracellular vesicles (EVs) are nanoscale vesicles released by various cells and deliver bioactive molecules to target cells, thereby mediating various processes, including the development of NAFLD. SCOPE OF REVIEW There is still a long way to actualize the application of EVs in NAFLD diagnosis and treatment. Herein, we summarize the roles of EVs in NAFLD and highlight their prospects for clinical application as a novel noninvasive diagnostic tool as well as a promising therapy for NAFLD, owing to their unique physiochemical characteristics. We summarize the literatures on the mechanisms by which EVs act as mediators of intercellular communication by regulating metabolism, insulin resistance, inflammation, immune response, intestinal microecology, and fibrosis in NAFLD. We also discuss future challenges that must be resolved to improve the therapeutic potential of EVs. MAJOR CONCLUSIONS The levels and contents of EVs change dynamically at different stages of diseases and this phenomenon may be exploited for establishing sensitive stage-specific markers. EVs also have high application potential as drug delivery systems with low immunogenicity and high biocompatibility and can be easily engineered. Research on the mechanisms and clinical applications of EVs in NAFLD is in its initial phase and the applicability of EVs in NAFLD diagnosis and treatment is expected to grow with technological progress.
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Affiliation(s)
- Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Youhui Xu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jou-Chen Chen
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Yi-Hung Lee
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Yushin Hu
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
- NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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26
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Carannante V, Wiklund M, Önfelt B. In vitro models to study natural killer cell dynamics in the tumor microenvironment. Front Immunol 2023; 14:1135148. [PMID: 37457703 PMCID: PMC10338882 DOI: 10.3389/fimmu.2023.1135148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Immunotherapy is revolutionizing cancer therapy. The rapid development of new immunotherapeutic strategies to treat solid tumors is posing new challenges for preclinical research, demanding novel in vitro methods to test treatments. Such methods should meet specific requirements, such as enabling the evaluation of immune cell responses like cytotoxicity or cytokine release, and infiltration into the tumor microenvironment using cancer models representative of the original disease. They should allow high-throughput and high-content analysis, to evaluate the efficacy of treatments and understand immune-evasion processes to facilitate development of new therapeutic targets. Ideally, they should be suitable for personalized immunotherapy testing, providing information for patient stratification. Consequently, the application of in vitro 3-dimensional (3D) cell culture models, such as tumor spheroids and organoids, is rapidly expanding in the immunotherapeutic field, coupled with the development of novel imaging-based techniques and -omic analysis. In this paper, we review the recent advances in the development of in vitro 3D platforms applied to natural killer (NK) cell-based cancer immunotherapy studies, highlighting the benefits and limitations of the current methods, and discuss new concepts and future directions of the field.
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Affiliation(s)
- Valentina Carannante
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Martin Wiklund
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Björn Önfelt
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
- Center for Infectious Medicine, Department of Medicine Huddinge, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
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27
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Ziegler AE, Fittje P, Müller LM, Ahrenstorf AE, Hagemann K, Hagen SH, Hess LU, Niehrs A, Poch T, Ravichandran G, Löbl SM, Padoan B, Brias S, Hennesen J, Richard M, Richert L, Peine S, Oldhafer KJ, Fischer L, Schramm C, Martrus G, Bunders MJ, Altfeld M, Lunemann S. The co-inhibitory receptor TIGIT regulates NK cell function and is upregulated in human intrahepatic CD56 bright NK cells. Front Immunol 2023; 14:1117320. [PMID: 36845105 PMCID: PMC9948018 DOI: 10.3389/fimmu.2023.1117320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/17/2023] [Indexed: 02/11/2023] Open
Abstract
The crosstalk between NK cells and their surrounding environment is enabled through activating and inhibitory receptors, which tightly control NK cell activity. The co-inhibitory receptor TIGIT decreases NK cell cytotoxicity and is involved in NK cell exhaustion, but has also been associated with liver regeneration, highlighting that the contribution of human intrahepatic CD56bright NK cells in regulating tissue homeostasis remains incompletely understood. A targeted single-cell mRNA analysis revealed distinct transcriptional differences between matched human peripheral blood and intrahepatic CD56bright NK cells. Multiparameter flow cytometry identified a cluster of intrahepatic NK cells with overlapping high expression of CD56, CD69, CXCR6, TIGIT and CD96. Intrahepatic CD56bright NK cells also expressed significantly higher protein surface levels of TIGIT, and significantly lower levels of DNAM-1 compared to matched peripheral blood CD56bright NK cells. TIGIT+ CD56bright NK cells showed diminished degranulation and TNF-α production following stimulation. Co-incubation of peripheral blood CD56bright NK cells with human hepatoma cells or primary human hepatocyte organoids resulted in migration of NK cells into hepatocyte organoids and upregulation of TIGIT and downregulation of DNAM-1 expression, in line with the phenotype of intrahepatic CD56bright NK cells. Intrahepatic CD56bright NK cells represent a transcriptionally, phenotypically, and functionally distinct population of NK cells that expresses higher levels of TIGIT and lower levels of DNAM-1 than matched peripheral blood CD56bright NK cells. Increased expression of inhibitory receptors by NK cells within the liver environment can contribute to tissue homeostasis and reduction of liver inflammation.
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Affiliation(s)
- Annerose E. Ziegler
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pia Fittje
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Luisa M. Müller
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Annika E. Ahrenstorf
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Kerri Hagemann
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Sven H. Hagen
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Leonard U. Hess
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Annika Niehrs
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Tobias Poch
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gevitha Ravichandran
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sebastian M. Löbl
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Benedetta Padoan
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Sébastien Brias
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jana Hennesen
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Myrtille Richard
- University of Bordeaux, Institut National de la Santé et de la Recherche Médicale, Bordeaux Population Health Research Center, UMR1219 and Inria, Team Statistics in systems biology and translationnal medicine (SISTM), Bordeaux, France
| | - Laura Richert
- University of Bordeaux, Institut National de la Santé et de la Recherche Médicale, Bordeaux Population Health Research Center, UMR1219 and Inria, Team Statistics in systems biology and translationnal medicine (SISTM), Bordeaux, France
| | - Sven Peine
- Institute for Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karl J. Oldhafer
- Department of General and Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Hamburg, Germany
| | - Lutz Fischer
- Department of Visceral Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Glòria Martrus
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Madeleine J. Bunders
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marcus Altfeld
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Sebastian Lunemann
- Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
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Zhao R, Zhao H, Guo Q, Mu Y, Zhang J, Su Y, Han Q. Edaravone protects against liver fibrosis progression via decreasing the IL-1β secretion of macrophages. Chem Biol Interact 2022; 368:110251. [PMID: 36343683 DOI: 10.1016/j.cbi.2022.110251] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/22/2022] [Accepted: 11/02/2022] [Indexed: 11/06/2022]
Abstract
Edaravone (EDA), a strong novel free radical scavenger, have been demonstrated to exert neurovascular protective effects clinically. Furthermore, EDA can suppress the lung injury, pulmonary fibrosis and skin fibrosis, while the precise effects and mechanisms of EDA on liver injury and fibrosis remain unclear. The effects of EDA on the Thioacetamide (TAA)-induced liver fibrosis were evaluated by sirius red staining, α-SMA immunohistochemistry. The percentages of immune cell subsets were analyzed by flow cytometry. Immunofluorescence assay was performed to identify the fibrotic properties of hepatic stellate cells (HSCs). Western blot and qPCR were used to detect the levels of liver fibrosis-related molecules and IL-1β. EDA displayed a hepatic protective role in TAA-induced chronic liver fibrosis via inhibiting monocyte/macrophages recruitment and IL-1β production of macrophages. Mechanically, EDA inhibited of NF-κB signal pathway and reactive oxygen species (ROS) production in macrophages. Moreover, EDA treatment indirectly suppressed the activation of HSCs by decreasing the IL-1β secretion of macrophages. Together, EDA protects against TAA-induced liver fibrosis via decreasing the IL-1β production of macrophages, thereby providing a feasible solution for clinical treatment of liver fibrosis.
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Affiliation(s)
- Rongrong Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Quanjuan Guo
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Yongliang Mu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Yuhang Su
- Department of Emergency Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China.
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China.
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29
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Yoon JS, Lee CW. Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma. Exp Mol Med 2022; 54:1799-1813. [PMID: 36380016 PMCID: PMC9722691 DOI: 10.1038/s12276-022-00883-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is a complicated heterogeneous organ composed of different cells. Parenchymal cells called hepatocytes and various nonparenchymal cells, including immune cells and stromal cells, are distributed in liver lobules with hepatic architecture. They interact with each other to compose the liver microenvironment and determine its characteristics. Although the liver microenvironment maintains liver homeostasis and function under healthy conditions, it also shows proinflammatory and profibrogenic characteristics that can induce the progression of hepatitis and hepatic fibrosis, eventually changing to a protumoral microenvironment that contributes to the development of hepatocellular carcinoma (HCC). According to recent studies, phosphatases are involved in liver diseases and HCC development by regulating protein phosphorylation in intracellular signaling pathways and changing the activities and characteristics of liver cells. Therefore, this review aims to highlight the importance of protein phosphatases in HCC development and in the regulation of the cellular components in the liver microenvironment and to show their significance as therapeutic targets.
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Affiliation(s)
- Joon-Sup Yoon
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea
| | - Chang-Woo Lee
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea ,grid.264381.a0000 0001 2181 989XDepartment of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351 Republic of Korea
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30
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TNFα and IFNγ cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration. Proc Natl Acad Sci U S A 2022; 119:e2209976119. [PMID: 36279473 PMCID: PMC9636974 DOI: 10.1073/pnas.2209976119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
IFNγ is traditionally known as a proinflammatory cytokine with diverse roles in antimicrobial and antitumor immunity. Yet, findings regarding its sources and functions during the regeneration process following a sterile injury are conflicting. Here, we show that natural killer (NK) cells are the main source of IFNγ in regenerating muscle. Beyond this cell population, IFNγ production is limited to a small population of T cells. We further show that NK cells do not play a major role in muscle regeneration following an acute injury or in dystrophic mice. Surprisingly, the absence of IFNγ per se also has no effect on muscle regeneration following an acute injury. However, the role of IFNγ is partially unmasked when TNFα is also neutralized, suggesting a compensatory mechanism. Using transgenic mice, we showed that conditional inhibition of IFNGR1 signaling in muscle stem cells or fibro-adipogenic progenitors does not play a major role in muscle regeneration. In contrast to common belief, we found that IFNγ is not present in the early inflammatory phase of the regeneration process but rather peaks when macrophages are acquiring an anti-inflammatory phenotype. Further transcriptomic analysis suggests that IFNγ cooperates with TNFα to regulate the transition of macrophages from pro- to anti-inflammatory states. The absence of the cooperative effect of these cytokines on macrophages, however, does not result in significant regeneration impairment likely due to the presence of other compensatory mechanisms. Our findings support the arising view of IFNγ as a pleiotropic inflammatory regulator rather than an inducer of the inflammatory response.
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31
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Vyas M, Peigney D, Demehri S. Extracellular matrix-natural killer cell interactome: an uncharted territory in health and disease. Curr Opin Immunol 2022; 78:102246. [PMID: 36174410 DOI: 10.1016/j.coi.2022.102246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 08/27/2022] [Indexed: 01/29/2023]
Abstract
Extracellular matrix (ECM) constantly undergoes remodeling to maintain the tissue homeostasis and an impaired ECM remodeling is a hallmark of many diseases, including cancer, infections, and inflammatory disorders. ECM has recently become recognized to regulate the immune response in peripheral tissues. Most immune cells express a diverse array of ECM receptors that, upon engagement by their cognate ECM ligands, can regulate their movement and effector functions. Natural killer (NK) cells are innate lymphocytes capable of mounting a swift cytotoxic immunity against cancer and virally infected cells using germline-encoded activating and inhibitory receptors. Regulation of NK cell effector function by ECM proteins in peripheral tissues is an emerging field with major implications for maintaining tolerance in normal tissues and controlling solid cancers, viral infections, and inflammatory diseases. The development of novel therapeutics targeting ECM-NK cell interplay represents a promising strategy to promote health and combat many diseases affecting solid organs.
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Affiliation(s)
- Maulik Vyas
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Domitille Peigney
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Shadmehr Demehri
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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32
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Alsulami K, Sadouni M, Tremblay-Sher D, Baril JG, Trottier B, Dupuy FP, Chartrand-Lefebvre C, Tremblay C, Durand M, Bernard NF. High frequencies of adaptive NK cells are associated with absence of coronary plaque in cytomegalovirus infected people living with HIV. Medicine (Baltimore) 2022; 101:e30794. [PMID: 36197157 PMCID: PMC9509172 DOI: 10.1097/md.0000000000030794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
The objective of this study was to evaluate whether adaptive NKG2C+CD57+ natural killer (adapNK) cell frequencies are associated with pre-clinical coronary atherosclerosis in participants of the Canadian HIV and Aging Cohort Study. This cross-sectional study included 194 Canadian HIV and Aging Cohort Study participants aged ≥ 40 years of which 128 were cytomegalovirus (CMV)+ people living with HIV (PLWH), 8 were CMV-PLWH, 37 were CMV mono-infected individuals, and 21 were neither human immunodeficiency virus nor CMV infected. Participants were evaluated for the frequency of their adapNK cells and total plaque volume (TPV). TPV was assessed using cardiac computed tomography. Participants were classified as free of, or having, coronary atherosclerosis if their TPV was "0" and ">0," respectively. The frequency of adapNK cells was categorized as low, intermediate or high if they constituted <4.6%, between ≥4.6% and 20% and >20%, respectively, of the total frequency of CD3-CD56dim NK cells. The association between adapNK cell frequency and TPV was assessed using an adjusted Poisson regression analysis. A greater proportion of CMV+PLWH with TPV = 0 had high adapNK cell frequencies than those with TPV > 0 (61.90% vs 39.53%, P = .03) with a similar non-significant trend for CMV mono-infected participants (46.15% vs 34.78%). The frequency of adapNK cells was negatively correlated with TPV. A high frequency of adapNK cells was associated with a relative risk of 0.75 (95% confidence intervals 0.58, 0.97, P = .03) for presence of coronary atherosclerosis. This observation suggests that adapNK cells play a protective role in the development of coronary atherosclerotic plaques.
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Affiliation(s)
- Khlood Alsulami
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Medicine, McGill University, Montreal, QC, Canada
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Manel Sadouni
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
| | - Daniel Tremblay-Sher
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
| | - Jean-Guy Baril
- Clinique de Médecine Urbaine du Quartier Latin, Montreal, QC, Canada
| | - Benoit Trottier
- Clinique de Médecine Urbaine du Quartier Latin, Montreal, QC, Canada
| | - Franck P. Dupuy
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Carl Chartrand-Lefebvre
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
- Département de Radiologie, Radio-oncologie et Médecine Nucléaire, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada
| | - Cécile Tremblay
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
- Department of Microbiology Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada
| | - Madeleine Durand
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
- Department of Microbiology Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada
| | - Nicole F. Bernard
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Medicine, McGill University, Montreal, QC, Canada
- Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Clinical Immunology, McGill University Health Centre, Montreal, QC, Canada
- *Correspondence: Nicole F. Bernard, Research Institute of the McGill University Health Centre, Glen site, Bloc E, 1001 Decarie Blvd., Room EM3.3238, Montreal, QC H4A 3J1, Canada (e-mail: )
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Ruiz-Cortes K, Villageliu DN, Samuelson DR. Innate lymphocytes: Role in alcohol-induced immune dysfunction. Front Immunol 2022; 13:934617. [PMID: 36105802 PMCID: PMC9464604 DOI: 10.3389/fimmu.2022.934617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Alcohol use is known to alter the function of both innate and adaptive immune cells, such as neutrophils, macrophages, B cells, and T cells. Immune dysfunction has been associated with alcohol-induced end-organ damage. The role of innate lymphocytes in alcohol-associated pathogenesis has become a focus of research, as liver-resident natural killer (NK) cells were found to play an important role in alcohol-associated liver damage pathogenesis. Innate lymphocytes play a critical role in immunity and homeostasis; they are necessary for an optimal host response against insults including infections and cancer. However, the role of innate lymphocytes, including NK cells, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, gamma delta T cells, and innate lymphoid cells (ILCs) type 1–3, remains ill-defined in the context of alcohol-induced end-organ damage. Innate-like B lymphocytes including marginal zone B cells and B-1 cells have also been identified; however, this review will address the effects of alcohol misuse on innate T lymphocytes, as well as the consequences of innate T-lymphocyte dysfunction on alcohol-induced tissue damage.
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Qian Y, Shang Z, Gao Y, Wu H, Kong X. Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells. Cell Mol Gastroenterol Hepatol 2022; 14:971-981. [PMID: 35738473 PMCID: PMC9489753 DOI: 10.1016/j.jcmgh.2022.05.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/28/2022] [Accepted: 07/27/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial hepatectomy and acute liver injury have been well-described. However, in patients with chronic and severe liver injury, the remnant liver cannot completely restore the liver mass and function, thereby involving liver progenitor-like cells (LPLCs) and various immune cells. RESULTS Macrophages are beneficial to LPLCs proliferation and the differentiation of LPLCs to hepatocytes. Also, cells expressing natural killer (NK) cell markers have been studied in promoting both liver injury and liver regeneration. NK cells can promote LPLC-induced liver regeneration, but the excessive activation of hepatic NK cells may lead to high serum levels of interferon-γ, thus inhibiting liver regeneration. CONCLUSIONS This review summarizes the recent research on 2 important innate immune cells, macrophages and NK cells, in LPLC-induced liver regeneration and the mechanisms of liver regeneration during chronic liver injury, as well as the latest macrophage- and NK cell-based therapies for chronic liver injury. These novel findings can further help identify new treatments for chronic liver injury, saving patients from the pain of liver transplantations.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi Shang
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Sajid M, Liu L, Sun C. The Dynamic Role of NK Cells in Liver Cancers: Role in HCC and HBV Associated HCC and Its Therapeutic Implications. Front Immunol 2022; 13:887186. [PMID: 35669776 PMCID: PMC9165341 DOI: 10.3389/fimmu.2022.887186] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/12/2022] [Indexed: 11/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains an important complication of chronic liver disease, especially when cirrhosis occurs. Existing treatment strategies include surgery, loco-regional techniques, and chemotherapy. Natural killer cells are distinctive cytotoxic lymphocytes that play a vital role in fighting tumors and infections. As an important constituent of the innate immune system against cancer, phenotypic and functional deviations of NK cells have been demonstrated in HCC patients who also exhibit perturbation of the NK-activating receptor/ligand axis. The rate of recurrence of tumor-infiltrating and circulating NK cells are positively associated with survival benefits in HCC and have prognostic significance, suggesting that NK cell dysfunction is closely related to HCC progression. NK cells are the first-line effector cells of viral hepatitis and play a significant role by directly clearing virus-infected cells or by activating antigen-specific T cells by producing IFN-γ. In addition, chimeric antigen receptor (CAR) engineered NK cells suggest an exclusive opportunity to produce CAR-NKs with several specificities with fewer side effects. In the present review, we comprehensively discuss the innate immune landscape of the liver, particularly NK cells, and the impact of tumor immune microenvironment (TIME) on the function of NK cells and the biological function of HCC. Furthermore, the role of NK cells in HCC and HBV-induced HCC has also been comprehensively elaborated. We also elaborate on available NK cell-based immunotherapeutic approaches in HCC treatment and summarize current advancements in the treatment of HCC. This review will facilitate researchers to understand the importance of the innate immune landscape of NK cells and lead to devising innovative immunotherapeutic strategies for the systematic treatment of HCC.
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Affiliation(s)
- Muhammad Sajid
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
- Transplant and Immunology Laboratory, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
| | - Cheng Sun
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
- Transplant and Immunology Laboratory, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, University of Science and Technology of China, Hefei, China
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Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci 2022; 23:ijms23073778. [PMID: 35409139 PMCID: PMC8998420 DOI: 10.3390/ijms23073778] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.
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Cross-Sectional and Time-Dependent Analyses on Inflammatory Markers Following Natural Killer Cell Activity. Diagnostics (Basel) 2022; 12:diagnostics12020448. [PMID: 35204539 PMCID: PMC8870889 DOI: 10.3390/diagnostics12020448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/01/2022] [Accepted: 02/07/2022] [Indexed: 02/01/2023] Open
Abstract
The function of natural killer (NK) cells in inflammation has not been explored enough in large-scale population studies. The cross-sectional and time-dependent relationship between NK cell activity (NKA) and inflammatory markers was examined. Methods: A total of 7031 subjects were involved in the cross-sectional analyses. Non-linear relationship between NKA and inflammatory indices was analyzed using generalized additive models. The time-dependent changes were analyzed in 1005 subjects with repeated measurement in 3–6 months. The changes in inflammatory markers were analyzed based on the changes in NKA. Results: As NKA reduces to a very low level, the white blood cell (WBC) and neutrophil counts increase sharply, and the lymphocyte count exhibits a slow decline. With increasing NKA larger than about 500 pg/mL, WBC and neutrophil-lymphocyte ratio (NLR) reduces in a mild slope. Among the subjects with repeated measurements, the follow-up NKA was increased with advancing baseline NKA levels. The subjects with a reduction in NKA indicated increment in WBC count, neutrophil count, and NLR, and decrease in lymphocyte count. Conclusions: Very low levels of NKA suggest a high inflammatory immune response. The changes in NKA may interact with the balance between neutrophils and lymphocytes.
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Dastagir N, Beal Z, Godwin J. Tissue origin of cytotoxic natural killer cells dictates their differential roles in mouse digit tip regeneration and progenitor cell survival. Stem Cell Reports 2022; 17:633-648. [PMID: 35120621 PMCID: PMC9039750 DOI: 10.1016/j.stemcr.2022.01.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 02/08/2023] Open
Abstract
Regeneration of amputated digit tips relies on mesenchymal progenitor cells and their differentiation into replacement bone and tissue stroma. Natural killer (NK) cells have well-characterized roles in antigen-independent killing of virally infected, pre-tumorous, or stressed cells; however, the potential for cytotoxic activity against regenerative progenitor cells is unclear. We identified NK cell recruitment to the regenerating digit tip, and NK cytotoxicity was observed against osteoclast and osteoblast progenitors. Adoptive cell transplants of spleen NK (SpNK) or thymus NK (ThNK) donor cells into immunodeficient mice demonstrated ThNK cell-induced apoptosis with a reduction in osteoclasts, osteoblasts, and proliferative cells, resulting in inhibition of regeneration. Adoptive transfer of NK cells deficient in NK cell activation genes identified that promotion of regeneration by SpNK cells requires Ncr1, whereas inhibition by ThNK cells is mediated via Klrk1 and perforin. Successful future therapies aimed at enhancing regeneration will require a deeper understanding of progenitor cell protection from NK cell cytotoxicity.
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Affiliation(s)
- Nadjib Dastagir
- The Jackson Laboratory, Bar Harbor, ME 04609, USA,Mount Desert Island Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Salisbury Cove, ME 04609, USA,Medical School of Hanover, 30659 Hannover, Germany
| | - Zachery Beal
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - James Godwin
- The Jackson Laboratory, Bar Harbor, ME 04609, USA,Mount Desert Island Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and Aging, Salisbury Cove, ME 04609, USA,Corresponding author
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Lian G, Mak TSK, Yu X, Lan HY. Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors. Int J Mol Sci 2021; 23:164. [PMID: 35008589 PMCID: PMC8745474 DOI: 10.3390/ijms23010164] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/08/2021] [Accepted: 12/20/2021] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent preclinical advances and the latest clinical outcomes of NK-based immunotherapies, as well as promising strategies to optimize current NK-targeted immunotherapies for solid tumors.
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Affiliation(s)
- Guangyu Lian
- Guangdong-Hong Kong Joint Research Laboratory on Immunological and Genetic Kidney Diseases, Department of Pathology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China;
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
- Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China;
| | - Thomas Shiu-Kwong Mak
- Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China;
| | - Xueqing Yu
- Guangdong-Hong Kong Joint Research Laboratory on Immunological and Genetic Kidney Diseases, Department of Pathology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China;
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Hui-Yao Lan
- Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China;
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Liu X, Zhong G, Li W, Zeng Y, Wu M. The Construction and Comprehensive Analysis of a ceRNA Immunoregulatory Network and Tissue-Infiltrating Immune Cells in Atrial Fibrillation. Int J Gen Med 2021; 14:9051-9066. [PMID: 34876841 PMCID: PMC8643171 DOI: 10.2147/ijgm.s338797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Background At present, the mechanisms behind atrial fibrillation (AF) pathogenesis are still unclear. We construct a ceRNA immunoregulatory network to further understand the mechanism of AF. Methods Four AF mRNA datasets from the Gene Expression Omnibus (GEO) database were integrated by SVA method. AF-related immune genes (AF-IRGs) were selected via combining ImmPort database with the genes in the module most associated with AF obtained by a weighted gene coexpression network analysis (WGCNA). Then, circRNA and miRNA expressions from the GEO database were extracted and mapped with related databases. Next, an immune-related circRNA-miRNA-mRNA ceRNA network was constructed and hub genes were filtered from a protein–protein interaction (PPI) network, and the differentially expressed (DE) hub genes in AF were further screened. Additionally, immune infiltration was investigated in AF by using CIBERSORT. Subsequently, the relationships between DE hub genes and AF-related infiltrating immune cells were performed by using Pearson correlation coefficients. Ulteriorly, the immune-cells-related ceRNA subnetwork in AF was built. Results A total of 95 AF-IRGs were detected, and an immune-related ceRNA network in AF was constructed with 12 circRNAs, 7 miRNAs and 50 mRNAs. The immune infiltration analysis indicated that a higher level of neutrophils, as well as a lower level of T cells regulatory (Tregs) and NK cells activated in AF. Four DE hub genes (CXCL12, IL7R, TNFSF13B, CD8A) were associated with Tregs or NK cells activated immune cells (P < 0.05). Tregs or NK cells activated immune cells-related ceRNA subnetwork including 5 circRNAs (has_circ_0001190, has_circ_0006725, has_circ_0079284, has_circ_0005299, and has_circ_0002103), 4 miRNAs (has-miR-198, has-miR-623, has-miR-1246, and has-miR-339-3p) and 4 DE hub genes was eventually constructed in AF. Conclusion Our results provide new insights into the molecular mechanisms governing AF progression from the perspective of immune-related ceRNA network.
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Affiliation(s)
- Xing Liu
- Department of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, People's Republic of China
| | - Guoqiang Zhong
- Department of Cardiology, Guangxi Cardiovascular Institute, The First Affiliated Hospital of Guangxi Medical University, Guangxi, People's Republic of China
| | - Wenbin Li
- Department of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, People's Republic of China
| | - Yiqian Zeng
- Department of Critical Care Medicine, Zhuzhou Central Hospital, Zhuzhou, Hunan, People's Republic of China
| | - Mingxing Wu
- Department of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, People's Republic of China
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Immunomodulatory Actions of Mesenchymal Stromal Cells (MSCs) in Osteoarthritis of the Knee. OSTEOLOGY 2021. [DOI: 10.3390/osteology1040020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Cellular therapy offers regeneration which curbs osteoarthritis of the knee. Among cellular therapies, mesenchymal stromal cells (MSCs) are readily isolated from various sources as culture expanded and unexpanded cellular population which are used as therapeutic products. Though MSCs possess a unique immunological and regulatory profile through cross-talk between MSCs and immunoregulatory cells (T cells, NK cells, dendritic cells, B cells, neutrophils, monocytes, and macrophages), they provide an immunotolerant environment when transplanted to the site of action. Immunophenotypic profile allows MSCs to escape immune surveillance and promotes their hypoimmunogenic or immune-privileged status. MSCs do not elicit a proliferative response when co-cultured with allogeneic T cells in vitro. MSCs secrete a wide range of anti-inflammatory mediators such as PGE-2, IDO, IL-1Ra, and IL-10. They also stimulate the resilient chondrogenic progenitors and enhance the chondrocyte differentiation by secretion of BMPs and TGFβ1. We highlight the various mechanisms of MSCs during tissue healing signals, their interaction with the immune system, and the impact of their lifespan in the management of osteoarthritis of the knee. A better understanding of the immunobiology of MSC renders them as an efficient therapeutic product for the management of osteoarthritis of the knee.
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Grimm C, Dickel S, Grundmann J, Payen D, Schanz J, Zautner AE, Tampe B, Moerer O, Winkler MS. Case Report: Interferon- γ Rescues Monocytic Human Leukocyte Antigen Receptor (mHLA-DR) Function in a COVID-19 Patient With ARDS and Superinfection With Multiple MDR 4MRGN Bacterial Strains. Front Immunol 2021; 12:753849. [PMID: 34790197 PMCID: PMC8591280 DOI: 10.3389/fimmu.2021.753849] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022] Open
Abstract
Background CD14+ monocytes present antigens to adaptive immune cells via monocytic human leukocyte antigen receptor (mHLA-DR), which is described as an immunological synapse. Reduced levels of mHLA-DR can display an acquired immune defect, which is often found in sepsis and predisposes for secondary infections and fatal outcomes. Monocytic HLA-DR expression is reliably induced by interferon- γ (IFNγ) therapy. Case Report We report a case of multidrug-resistant superinfected COVID-19 acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation (ECMO) support. The resistance profiles of the detected Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Citrobacter freundii isolates were equipped with resistance to all four antibiotic classes including carbapenems (4MRGN) and Cefiderocol in the case of K. pneumoniae. A causal therapeutic antibiotic strategy was not available. Therefore, we measured the immune status of the patient aiming to identify a potential acquired immune deficiency. Monocyte HLA-DR expression identified by FACS analysis revealed an expression level of 34% positive monocytes and suggested severe immunosuppression. We indicated IFNγ therapy, which resulted in a rapid increase in mHLA-DR expression (96%), rapid resolution of invasive bloodstream infection, and discharge from the hospital on day 70. Discussion Superinfection is a dangerous complication of COVID-19 pneumonia, and sepsis-induced immunosuppression is a risk factor for it. Immunosuppression is expressed by a disturbed antigen presentation of monocytes to cells of the adaptive immune system. The case presented here is remarkable as no validated antibiotic regimen existed against the detected bacterial pathogens causing bloodstream infection and severe pneumonia in a patient suffering from COVID-19 ARDS. Possible restoration of the patient's own immunity by IFNγ was a plausible option to boost the patient's immune system, eliminate the identified 4MRGNs, and allow for lung recovery. This led to the conclusion that immune status monitoring is useful in complicated COVID-19-ARDS and that concomitant IFNγ therapy may support antibiotic strategies. Conclusion After a compromised immune system has been detected by suppressed mHLA-DR levels, the immune system can be safely reactivated by IFNγ.
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Affiliation(s)
- Clemens Grimm
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Steffen Dickel
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Julian Grundmann
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Didier Payen
- Université Paris 7 Cité Sorbonne, UMR INSERM 1160, Paris, France
| | - Julie Schanz
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Andreas Erich Zautner
- Department of Medical Microbiology and Virology, University Medical Center Göttingen, Göttingen, Germany
| | - Björn Tampe
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany
| | - Onnen Moerer
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
| | - Martin Sebastian Winkler
- Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
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Li X, Han J, Liu Y, Liang H. Lactobacillus casei relieves liver injury by regulating immunity and suppression of the enterogenic endotoxin-induced inflammatory response in rats cotreated with alcohol and iron. Food Sci Nutr 2021; 9:5391-5401. [PMID: 34646510 PMCID: PMC8497841 DOI: 10.1002/fsn3.2486] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/28/2021] [Accepted: 07/09/2021] [Indexed: 11/30/2022] Open
Abstract
Excessive alcohol and iron intake can reportedly cause liver damage. In the present study, we investigated the effect of Lactobacillus casei on liver injury in rats co-exposed to alcohol and iron and evaluated its possible mechanism. Sixty male Wistar rats were randomly divided into three groups for 12 weeks: the Control group (administered normal saline by gavage and provided a normal diet); alcohol +iron group (Model group, treated with alcohol [3.5-5.3 g/kg/day] by gavage and dietary iron [1,500 mg/kg]); Model group supplemented with L. casei (8 × 108 CFU kg-1 day-1) (L. casei group). Using hematoxylin and eosin (HE) staining and transmission electron microscopy, we observed that L. casei supplementation could alleviate disorders associated with lipid metabolism, inflammation, and intestinal mucosal barrier injury. Moreover, levels of serum alanine aminotransferase, gamma-glutamyl transferase, triglyceride (TG), and hepatic TG were significantly increased in the model group; however, these levels were significantly decreased following the 12-week L. casei supplementation. In addition, we observed notable improvements in intestinal mucosal barrier function and alterations in T lymphocyte subsets and natural killer cells in L. casei-treated rats when compared with the model group. Furthermore, L. casei intervention alleviated serum levels of tumor necrosis factor-α and interleukin-1β, accompanied by decreased serum endotoxin levels and downregulated expression of toll-like receptor 4 and its related molecules MyD88, nuclear factor kappa-B p65, and TNF-α. Accordingly, supplementation with L. casei could effectively improve liver injury induced by the synergistic interaction between alcohol and iron. The underlying mechanism for this improvement may be related to immune regulation and inhibition of enterogenic endotoxin-mediated inflammation.
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Affiliation(s)
- Xuelong Li
- Department of Human NutritionCollege of Public HealthQingdao UniversityQingdaoChina
- Department of Clinical NutritionThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Jianmin Han
- Department of Human NutritionCollege of Public HealthQingdao UniversityQingdaoChina
| | - Ying Liu
- Basic Medical CollegeQingdao UniversityQingdaoChina
| | - Hui Liang
- Department of Human NutritionCollege of Public HealthQingdao UniversityQingdaoChina
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Shanley LC, Mahon OR, Kelly DJ, Dunne A. Harnessing the innate and adaptive immune system for tissue repair and regeneration: Considering more than macrophages. Acta Biomater 2021; 133:208-221. [PMID: 33657453 DOI: 10.1016/j.actbio.2021.02.023] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 02/05/2021] [Accepted: 02/15/2021] [Indexed: 02/08/2023]
Abstract
Tissue healing and regeneration is a complex, choreographed, spatiotemporal process involving a plethora of cell types, the activity of which is stringently regulated in order for effective tissue repair to ensue post injury. A number of globally prevalent conditions such as heart disease, organ failure, and severe musculoskeletal disorders require new therapeutic strategies to repair damaged or diseased tissue, particularly given an ageing population in which obesity, diabetes, and consequent tissue defects have reached epidemic proportions. This is further compounded by the lack of intrinsic healing and poor regenerative capacity of certain adult tissues. While vast progress has been made in the last decade regarding tissue regenerative strategies to direct self-healing, for example, through implantation of tissue engineered scaffolds, several challenges have hampered the clinical application of these technologies. Control of the immune response is growing as an attractive approach in regenerative medicine and it is becoming increasingly apparent that an in depth understanding of the interplay between cells of the immune system and tissue specific progenitor cells is of paramount importance. Furthermore, the integration of immunology and bioengineering promises to elevate the efficacy of biomaterial-based tissue repair and regeneration. In this review, we highlight the role played by individual immune cell subsets in tissue repair processes and describe new approaches that are being taken to direct appropriate healing outcomes via biomaterial mediated targeting of immune cell activity. STATEMENT OF SIGNIFICANCE: It is becoming increasingly apparent that controlling the immune response is as an attractive approach in regenerative medicine. Here, we propose that an in-depth understanding of immune system and tissue specific progenitor cell interactions may reveal mechanisms by which tissue healing and regeneration takes place, in addition to identifying novel therapeutic targets that could be used to enhance the tissue repair process. To date, most reviews have focused solely on macrophage subsets. This manuscript details the role of other innate and adaptive immune cells such as innate lymphoid cells (ILCs), natural killer (NK) cells and γδT cells (in addition to macrophages) in tissue healing. We also describe new approaches that are being taken to direct appropriate healing outcomes via biomaterial mediated cytokine and drug delivery.
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Ping J, Zhou C, Dong Y, Wu X, Huang X, Sun B, Zeng B, Xu F, Liang W. Modulating immune microenvironment during bone repair using biomaterials: Focusing on the role of macrophages. Mol Immunol 2021; 138:110-120. [PMID: 34392109 DOI: 10.1016/j.molimm.2021.08.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/09/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022]
Abstract
Bone is a self-regenerative tissue that can repair small defects and fractures. In large defects, bone tissue is unable to provide nutrients and oxygen for repair, and autologous grafting is used as the gold standard. As an alternative method, the bone tissue regeneration approach uses osteoconductive biomaterials to overcome bone graft disadvantages. However, biomaterials are considered as foreign components that can stimulate host immune responses. Although traditional principles have been aimed to minimize immune reactions, the design of biomaterials has steadily shifted toward creating an immunomodulatory microenvironment to harness immune cells and responses to repair damaged tissue. Among immune cells, macrophages secrete various immunomodulatory mediators and crosstalk with bone-forming cells and play key roles in bone tissue engineering. Macrophage polarization toward M1 and M2 subtypes mediate pro-inflammatory and anti-inflammatory responses, respectively, which are crucial for bone repairing at different stages. This review provides an overview of the crosstalk between various immune cells and biomaterials, macrophage polarization, and the effect of physicochemical properties of biomaterials on the immune responses, especially macrophages, in bone tissue engineering.
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Affiliation(s)
- Jianfeng Ping
- Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang Province, PR China
| | - Chao Zhou
- Department of Orthopedics, Zhoushan Guanghua Hospital, Zhoushan 316000, Zhejiang Province, PR China
| | - Yongqiang Dong
- Department of Orthopaedics, Xinchang People's Hospital, Shaoxing 312500, Zhejiang Province, PR China
| | - Xudong Wu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Xiaogang Huang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Bin Sun
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Bin Zeng
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Fangming Xu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China.
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China.
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Huang Y, Oldham JM, Ma SF, Unterman A, Liao SY, Barros AJ, Bonham CA, Kim JS, Vij R, Adegunsoye A, Strek ME, Molyneaux PL, Maher TM, Herazo-Maya JD, Kaminski N, Moore BB, Martinez FJ, Noth I. Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells. Am J Respir Crit Care Med 2021; 204:197-208. [PMID: 33689671 PMCID: PMC8650792 DOI: 10.1164/rccm.202008-3093oc] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 03/08/2021] [Indexed: 11/16/2022] Open
Abstract
Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objectives: To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. Measurements and Main Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with a cross-sectional model. The FVC predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.
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Affiliation(s)
- Yong Huang
- Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia
| | - Justin M. Oldham
- Division of Pulmonary, Critical Care, and Sleep Medicine, The University of California at Davis, Sacramento, California
| | - Shwu-Fan Ma
- Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia
| | - Avraham Unterman
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Shu-Yi Liao
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - Andrew J. Barros
- Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia
| | - Catherine A. Bonham
- Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia
| | - John S. Kim
- Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia
| | - Rekha Vij
- Section of Pulmonary and Critical Care Medicine and
| | - Ayodeji Adegunsoye
- Section of Pulmonary and Critical Care Medicine and
- Department of Human Genetics, Genetics, Genomic and Systems Biology, University of Chicago, Chicago, Illinois
| | | | - Philip L. Molyneaux
- National Heart and Lung Institute, Imperial College, London, United Kingdom
- Royal Brompton Hospital, London, United Kingdom
| | - Toby M. Maher
- National Heart and Lung Institute, Imperial College, London, United Kingdom
- Royal Brompton Hospital, London, United Kingdom
- Division of Pulmonary, Critical Care and Sleep Medicine, Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jose D. Herazo-Maya
- Division of Pulmonary, Critical Care, and Sleep Medicine, Tampa General Hospital, University of South Florida, Tampa, Florida
| | - Naftali Kaminski
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Bethany B. Moore
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; and
| | - Fernando J. Martinez
- Internal Medicine, Weill Cornell Medical College, Cornell University, New York, New York
| | - Imre Noth
- Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia
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Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther 2021; 6:263. [PMID: 34248142 PMCID: PMC8273155 DOI: 10.1038/s41392-021-00658-5] [Citation(s) in RCA: 1262] [Impact Index Per Article: 315.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 05/11/2021] [Accepted: 05/23/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.
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Chirumbolo S, Valdenassi L, Simonetti V, Bertossi D, Ricevuti G, Franzini M, Pandolfi S. Insights on the mechanisms of action of ozone in the medical therapy against COVID-19. Int Immunopharmacol 2021; 96:107777. [PMID: 34020394 PMCID: PMC8112288 DOI: 10.1016/j.intimp.2021.107777] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/28/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023]
Abstract
An increasing amount of reports in the literature is showing that medical ozone (O3) is used, with encouraging results, in treating COVID-19 patients, optimizing pain and symptoms relief, respiratory parameters, inflammatory and coagulation markers and the overall health status, so reducing significantly how much time patients underwent hospitalization and intensive care. To date, aside from mechanisms taking into account the ability of O3 to activate a rapid oxidative stress response, by up-regulating antioxidant and scavenging enzymes, no sound hypothesis was addressed to attempt a synopsis of how O3 should act on COVID-19. The knowledge on how O3 works on inflammation and thrombosis mechanisms is of the utmost importance to make physicians endowed with new guns against SARS-CoV2 pandemic. This review tries to address this issue, so to expand the debate in the scientific community.
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Affiliation(s)
- Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
| | - Luigi Valdenassi
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy
| | - Vincenzo Simonetti
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy
| | - Dario Bertossi
- Department of Surgery, Dentistry, Paediatrics and Gynaecology Unit of Maxillo-Facial Surgery University of Verona, Verona, Italy
| | | | - Marianno Franzini
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy
| | - Sergio Pandolfi
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy; Villa Mafalda Clinics via Monte delle Gioie, Rome, Italy
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Li H, Chen C, Wang DW. Inflammatory Cytokines, Immune Cells, and Organ Interactions in Heart Failure. Front Physiol 2021; 12:695047. [PMID: 34276413 PMCID: PMC8281681 DOI: 10.3389/fphys.2021.695047] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/25/2021] [Indexed: 12/20/2022] Open
Abstract
Despite mounting evidence demonstrating the significance of inflammation in the pathophysiological mechanisms of heart failure (HF), most large clinical trials that target the inflammatory responses in HF yielded neutral or even worsening outcomes. Further in-depth understanding about the roles of inflammation in the pathogenesis of HF is eagerly needed. This review summarizes cytokines, cardiac infiltrating immune cells, and extracardiac organs that orchestrate the complex inflammatory responses in HF and highlights emerging therapeutic targets.
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Affiliation(s)
- Huihui Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ma C, Yan K, Wang Z, Zhang Q, Gao L, Xu T, Sai J, Cheng F, Du Y. The association between hypertension and nonalcoholic fatty liver disease (NAFLD): literature evidence and systems biology analysis. Bioengineered 2021; 12:2187-2202. [PMID: 34096467 PMCID: PMC8806441 DOI: 10.1080/21655979.2021.1933302] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue as its progression increases risks of multisystem morbidity and mortality. Recent evidence indicates a more complex relationship between hypertension and NAFLD than previously thought. In this study, a comprehensive literature search was used to gather information supporting the comorbidity phenomenon of hypertension and NAFLD. Then, systems biology approach was applied to identify the potential genes and mechanisms simultaneously associated with hypertension and NAFLD. With the help of protein-protein interaction network-based algorithm, we found that the distance between hypertension and NAFLD was much less than random ones. Sixty-four shared genes of hypertension and NAFLD modules were identified as core genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis indicated that some inflammatory, metabolic and endocrine signals were related to the potential biological functions of core genes. More importantly, drugs used to treat cardiovascular diseases, hypertension, hyperlipidemia, inflammatory diseases and depression could be potential therapeutics against hypertension-NAFLD co-occurrence. After analyzing public OMICs data, ALDH1A1 was identified as a potential therapeutic target, without being affected by reverse causality. These findings give a clue for the potential mechanisms of comorbidity of hypertension and NAFLD and highlight the multiple target-therapeutic strategy of NAFLD for future clinical research.
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Affiliation(s)
- Chongyang Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Kai Yan
- Department of Traditional Chinese Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zisong Wang
- Department of Traditional Chinese Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Qiuyun Zhang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Lianyin Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Tian Xu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiayang Sai
- Department of Oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Fafeng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuqiong Du
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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