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Hsieh LL, Thompson EA, Jairam NP, Roznik K, Figueroa A, Aytenfisu T, Zhou W, Gour N, Chao KH, Milstone AM, Egbert E, D'Alessio F, Karakousis PC, Ordoñez A, Scully EP, Pekosz A, Karaba AH, Cox AL. SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19. Sci Transl Med 2025; 17:eadn7527. [PMID: 40397714 DOI: 10.1126/scitranslmed.adn7527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 11/18/2024] [Accepted: 04/01/2025] [Indexed: 05/23/2025]
Abstract
Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1+ neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.
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Affiliation(s)
- Leon L Hsieh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Elizabeth A Thompson
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Nirvani P Jairam
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Katerina Roznik
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Alexis Figueroa
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tihitina Aytenfisu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Weiqiang Zhou
- Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Naina Gour
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kuan-Hao Chao
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Aaron M Milstone
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Emily Egbert
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Franco D'Alessio
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Petros C Karakousis
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Alvaro Ordoñez
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Eileen P Scully
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrew Pekosz
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Andrew H Karaba
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Pekayvaz K, Kilani B, Joppich M, Eivers L, Brambs S, Knottenberg V, Akgöl S, Yue K, Li L, Martinez-Navarro A, Kaiser R, Meißner N, Schulz H, Belz L, Akhalkatsi A, Stockhausen S, Mueller TT, Millonig S, Hartelt L, Gold C, Janjic A, Polewka V, Wendler F, Droste Zu Senden A, Titova A, Leunig A, Voelkl M, Engelmann B, Hernandez Petzsche MR, Boeckh-Behrens T, Liebig T, Winning S, Fandrey J, Dichgans M, Enard W, Zimmer R, Tiedt S, Massberg S, Nicolai L, Stark K. Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis and correlate with thrombus resolution. Immunity 2025; 58:1343-1358.e13. [PMID: 40280129 DOI: 10.1016/j.immuni.2025.03.020] [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: 08/30/2024] [Revised: 12/31/2024] [Accepted: 03/27/2025] [Indexed: 04/29/2025]
Abstract
Thrombotic diseases remain the major cause of death and disability worldwide, and the contribution of inflammation is increasingly recognized. Thromboinflammation has been identified as a key pathomechanism, but an unsupervised map of immune-cell states, trajectories, and intercommunication at a single-cell level has been lacking. Here, we reveal innate leukocyte substates with prominent thrombolytic properties by employing single-cell omics measures on human stroke thrombi. Using in vivo and in vitro thrombosis models, we propose a pro-resolving monocyte-neutrophil axis, combining two properties: (1) NR4A1hi non-classical monocytes acquire a thrombolytic and neutrophil-chemoattractive phenotype, and (2) blood neutrophils are thereby continuously recruited to established thrombi through CXCL8-CXCR1 and CXCR2 and adopt a hypoxia-induced thrombus-resolving urokinase receptor (PLAUR)+ phenotype. This immunothrombolytic axis results in thrombus resolution. Together, with this immune landscape of thrombosis, we provide a valuable resource and introduce the concept of "immunothrombolysis" with broad mechanistic and translational implications at the crossroad of inflammation and thrombosis.
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Affiliation(s)
- Kami Pekayvaz
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
| | - Badr Kilani
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Markus Joppich
- LFE Bioinformatik, Department of Informatics, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Luke Eivers
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Sophia Brambs
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | | | - Sezer Akgöl
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Keyang Yue
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Lukas Li
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | | | - Rainer Kaiser
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Nina Meißner
- Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
| | - Heiko Schulz
- Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Larissa Belz
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | | | - Sven Stockhausen
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Tonina T Mueller
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Simon Millonig
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Lea Hartelt
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Christoph Gold
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Aleksandar Janjic
- Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Vivien Polewka
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Franziska Wendler
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | | | - Anna Titova
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany
| | - Alexander Leunig
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Michael Voelkl
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Bernd Engelmann
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Moritz R Hernandez Petzsche
- Department of Diagnostic and Interventional Neuroradiology, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Tobias Boeckh-Behrens
- Department of Diagnostic and Interventional Neuroradiology, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Thomas Liebig
- Institute for Diagnostic and Interventional Neuroradiology, University Hospital, LMU Munich, Munich, Germany
| | - Sandra Winning
- University of Duisburg-Essen, Institute for Physiology, Essen, Germany
| | - Joachim Fandrey
- University of Duisburg-Essen, Institute for Physiology, Essen, Germany
| | - Martin Dichgans
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
| | - Wolfgang Enard
- Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Ralf Zimmer
- LFE Bioinformatik, Department of Informatics, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Steffen Tiedt
- Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
| | - Steffen Massberg
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Leo Nicolai
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
| | - Konstantin Stark
- Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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Wang LJ, Lei CL, Wang TA, Lin ZF, Feng SJ, Wei T, Li YQ, Shen MR, Li Y, Liao LF. Prognostic value of the preoperative systemic immune-inflammation nutritional index in patients with gastric cancer. World J Clin Oncol 2025; 16:102294. [PMID: 40290682 PMCID: PMC12019271 DOI: 10.5306/wjco.v16.i4.102294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/04/2024] [Accepted: 01/21/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths in China. Many patients with GC frequently experience symptoms related to the disease, including anorexia, nausea, vomiting, and other discomforts, and often suffer from malnutrition, which in turn negatively affects perioperative safety, prognosis, and the effectiveness of adjuvant therapeutic measures. Consequently, some nutritional indicators such as nutritional risk index (NRI), prognostic nutritional index (PNI), and systemic immune-inflammatory-nutritional index (SIINI) can be used as predictors of the prognosis of GC patients. AIM To examine the prognostic significance of PNI, NRI, and SIINI in postoperative patients with GC. METHODS A retrospective analysis was conducted on the clinical data of patients with GC who underwent surgical treatment at the Guangxi Medical University Cancer Hospital between January 2010 and December 2018. The area under the receiver operating characteristic (ROC) curve was assessed using ROC curve analysis, and the optimal cutoff values for NRI, PNI, and SIINI were identified using the You-Review-HTMLden index. Survival analysis was performed using the Kaplan-Meier method. In addition, univariate and multivariate analyses were conducted using the Cox proportional hazards regression model. RESULTS This study included a total of 803 patients. ROC curves were used to evaluate the prognostic ability of NRI, PNI, and SIINI. The results revealed that SIINI had superior predictive accuracy. Survival analysis indicated that patients with GC in the low SIINI group had a significantly better survival rate than those in the high SIINI group (P < 0.05). Univariate analysis identified NRI [hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.52-0.89, P = 0.05], PNI (HR = 0.60, 95%CI: 0.46-0.79, P < 0.001), and SIINI (HR = 2.10, 95%CI: 1.64-2.69, P < 0.001) as prognostic risk factors for patients with GC. However, multifactorial analysis indicated that SIINI was an independent risk factor for the prognosis of patients with GC (HR = 1.65, 95%CI: 1.26-2.16, P < 0.001). CONCLUSION Analysis of clinical retrospective data revealed that SIINI is a valuable indicator for predicting the prognosis of patients with GC. Compared with NRI and PNI, SIINI may offer greater application for prognostic assessment.
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Affiliation(s)
- Li-Jing Wang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Cai-Lu Lei
- School of Pharmaceutical Science, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ting-An Wang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Feng Lin
- School of Pharmaceutical Science, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Jie Feng
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Wei
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Qin Li
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Meng-Ru Shen
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan Li
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Liu-Feng Liao
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Shadmani A, Wu AY. Navigating the path to corneal healing success and challenges: a comprehensive overview. Eye (Lond) 2025; 39:1047-1055. [PMID: 39939391 PMCID: PMC11978883 DOI: 10.1038/s41433-025-03619-2] [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: 07/28/2024] [Revised: 12/16/2024] [Accepted: 01/14/2025] [Indexed: 02/14/2025] Open
Abstract
The cornea serves to protect the eye from external insults and refracts light to the retina. Maintaining ocular homeostasis requires constant epithelial renewal and an efficient healing process following injury. Corneal wound healing is a dynamic process involving several key cell populations and molecular pathways. Immediately after a large corneal epithelial injury involving limbal stem cells, conjunctival epithelial cells migrate toward the center of the wound guided by the newly formed electrical field (EF). Proliferation and transdifferentiation play a critical role in corneal epithelial regeneration. Corneal nerve endings migrate through the EF, connect with the migrating epithelial cells, and provide them with multiple growth factors. Finally, the migrated epithelial cells undergo differentiation, which is also regulated by corneal nerve endings. All these processes require energy and effective cellular cross-talk between different cell lines and extracellular matrix molecules. We provide an overview of the roles and interactions between corneal wound regeneration components that may help develop fascinating new targeted therapeutic strategies to enhance corneal wound healing with less injury-related corneal opacity and neovascularization.
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Affiliation(s)
- Athar Shadmani
- Bascom Palmer Eye Institute, University of Miami, Naples, FL, USA
- Omid Salmat Clinic, Firozabad, Shiraz University of Medical Sciences, Firozabad, Iran
| | - Albert Y Wu
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA.
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Renò F, Pagano CA, Bignotto M, Sabbatini M. Neutrophil Heterogeneity in Wound Healing. Biomedicines 2025; 13:694. [PMID: 40149670 PMCID: PMC11940162 DOI: 10.3390/biomedicines13030694] [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: 02/04/2025] [Revised: 03/06/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Neutrophils are the most abundant type of immune cells and also the most underestimated cell defenders in the human body. In fact, their lifespan has also been extensively revised in recent years, going from a half-life of 8-10 h to a longer lifespan of up to 5.4 days in humans; it has been discovered that their mechanisms of defense are multiple and finely modulated, and it has been suggested that the heterogeneity of neutrophils occurs as well as in other immune cells. Neutrophils also play a critical role in the wound healing process, and their involvement is not limited to the initial stages of defense against pathogens, but extends to the inflammatory phase of tissue reconstruction. Neutrophil heterogeneity has recently been reported at the presence of distinct subtypes expressing different functional states, which contribute uniquely to the different phases of innate immunity and wound healing. This heterogeneity can be induced by the local microenvironment, by the presence of specific cytokines and by the type of injury. The different functional states of neutrophils enable a finely tuned response to injury and stress, which is essential for effective healing. Understanding the functional heterogeneity of neutrophils in wound healing can unveil potential pathological profiles and therapeutic targets. Moreover, the understanding of neutrophil heterogeneity dynamics could help in designing strategies to manage excessive inflammation or impaired healing processes. This review highlights the complexity of neutrophil heterogeneity and its critical roles throughout the phases of wound healing.
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Affiliation(s)
- Filippo Renò
- Health Sciences Department (DiSS), San Paolo Hospital, Università di Milano, Via A. di Rudini 8, 20142 Milano, Italy; (F.R.); (M.B.)
| | - Corinna Anais Pagano
- Department of Science and Innovation Technology (DISIT), Università del Piemonte Orientale, Via T. Michel 11, 15121 Alessandria, Italy;
| | - Monica Bignotto
- Health Sciences Department (DiSS), San Paolo Hospital, Università di Milano, Via A. di Rudini 8, 20142 Milano, Italy; (F.R.); (M.B.)
| | - Maurizio Sabbatini
- Department of Science and Innovation Technology (DISIT), Università del Piemonte Orientale, Via T. Michel 11, 15121 Alessandria, Italy;
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Wang C, Liu X, Lv W, Kuang X, Wu F, Fan X, Pang Y. Long-lasting comfort ocular surface drug delivery by in situ formation of an adhesive lubricative Janus nanocoating. SCIENCE ADVANCES 2025; 11:eads0282. [PMID: 40053587 PMCID: PMC11887845 DOI: 10.1126/sciadv.ads0282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025]
Abstract
Topical drug delivery on ocular surface always suffers from frequent administration and low bioavailability due to short drug residence. Despite advances of different adhesive ophthalmic drugs in extending release, cornea and eyelid nonselective adhesion inevitably causes ocular discomfort and even damage. Here, we describe in situ formation of an adhesive lubricative Janus nanocoating (ALJN) to enable long-lasting comfort drug delivery. By iron complexation, an asymmetric ALJN is formed on ocular surface via facile sequential instillation. The adhesive polyphenol inner layer binding with ocular surface enables drug loading and sustained release, while the lubricative zwitterionic polymer outer layer prevents eyelid adhesion to ensure comfort. Following instillation, ALJN retains on ocular surface over 24 hours and reduces blinking frequency to normal level. Moreover, ALJN demonstrates remarkable therapeutic potential in mouse and rabbit models of corneal contusion and alkali burn. This work proposes a comfortable long-lasting topical delivery platform for treating various ocular diseases.
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Affiliation(s)
- Chuhan Wang
- Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Center for Basic Medical Research and Innovation in Visual System Diseases, Ministry of Education, Shanghai 200011, China
| | - Xiaobing Liu
- College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wenyan Lv
- College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xiao Kuang
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Feng Wu
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Center for Basic Medical Research and Innovation in Visual System Diseases, Ministry of Education, Shanghai 200011, China
| | - Yan Pang
- Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Center for Basic Medical Research and Innovation in Visual System Diseases, Ministry of Education, Shanghai 200011, China
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
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He W, Yan L, Hu D, Hao J, Liou Y, Luo G. Neutrophil heterogeneity and plasticity: unveiling the multifaceted roles in health and disease. MedComm (Beijing) 2025; 6:e70063. [PMID: 39845896 PMCID: PMC11751288 DOI: 10.1002/mco2.70063] [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: 09/02/2024] [Revised: 11/04/2024] [Accepted: 12/11/2024] [Indexed: 01/24/2025] Open
Abstract
Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.
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Affiliation(s)
- Weifeng He
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Lingfeng Yan
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Dongxue Hu
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Jianlei Hao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University)Jinan UniversityZhuhaiGuangdongChina
- The Biomedical Translational Research InstituteFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Yih‐Cherng Liou
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- National University of Singapore (NUS) Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore
| | - Gaoxing Luo
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
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8
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Xu X, Ying H, Wang X, Hong W, Zhang M. Identification of Angiogenesis-Related Gene Signatures and Prediction of Potential Therapeutic Targets in Ulcerative Colitis Using Integrated Bioinformatics. J Inflamm Res 2024; 17:11699-11717. [PMID: 39741751 PMCID: PMC11687120 DOI: 10.2147/jir.s478880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/10/2024] [Indexed: 01/03/2025] Open
Abstract
Objective This study aims to clarify angiogenesis mechanisms in ulcerative colitis and identify potential therapeutic targets. Methods The Gene Expression Omnibus (GEO) database was used to obtain expression profiles and clinical data for UC and healthy colon tissues. Angiogenesis-related gene sets were acquired from GeneCards. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified UC-associated hub genes. The CIBERSORT algorithm assessed immune cell infiltration. Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to determine biological mechanisms. External datasets were utilized to validate and characterize the angiogenesis-related genes in relation to biological agents. Additionally, an ulcerative colitis mouse model was constructed to verify the key genes' expression using real-time quantitative PCR. To predict potential therapeutic agents, we used the DGIdb database. Molecular docking modeled small molecule binding conformations to key gene targets. Results This study identified 1,247 DEGs enriched in inflammatory/immune pathways from UC and healthy colon samples. WGCNA indicated the black and light cyan modules were most relevant. Intersecting these with 89 angiogenesis genes revealed 5 UC-associated hub genes (pdgfrb, vegfc, angpt2, tnc, hgf). Validation via ROC analysis, differential expression, and a mouse model confirmed upregulation, supporting their potential as UC diagnostic biomarkers. Bioinformatics approaches like protein-protein interaction, enrichment analysis, and GSEA revealed involvement in PDGFR and PI3K-Akt signaling pathways. CIBERSORT analysis of immune cell infiltration showed positive correlations between the key genes and various immune cells, especially neutrophils, highlighting angiogenesis-inflammation interplay in UC. A ceRNA network was constructed. Drug prediction and molecular docking revealed potential UC therapies like sunitinib and imatinib targeting angiogenesis. Conclusion This study identified and validated five angiogenesis-related genes (pdgfrb, vegfc, angpt2, tnc, hgf) that may serve as diagnostic biomarkers and drug targets for UC.
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Affiliation(s)
- Xijuan Xu
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Hongan Ying
- Department of Geriatrics, Taizhou First People’s Hospital, Taizhou, People’s Republic of China
| | - Xiaozhi Wang
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Weiwen Hong
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Meng Zhang
- Department of General Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
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9
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Hou Y, Zhang W, Le VNH, Deng S, Hadrian K, Mestanoglu M, Musial G, Bock F, Cursiefen C. Efficacy and safety of combined UV-light corneal crosslinking and fine-needle diathermy to regress pathological murine corneal (lymph)angiogenesis in vivo. Acta Ophthalmol 2024; 102:e1002-e1010. [PMID: 38687167 DOI: 10.1111/aos.16696] [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: 08/21/2023] [Accepted: 04/08/2024] [Indexed: 05/02/2024]
Abstract
PURPOSE To compare safety and efficacy of isolated and combined UV-light corneal crosslinking (CXL) and fine-needle diathermy (FND) to regress pathological corneal vessels in vivo. METHODS Mice with inflamed and pathologically vascularized corneas received CXL or FND as monotherapy or a combination of both treatments. Corneal pathological blood and lymphatic vessels, immune cells and the morphology of anterior segment structures were evaluated. RESULTS All three approaches were able to regress blood and lymphatic vessels in mice. A comparative analysis of the three methods revealed that the FND monotherapy and the CXL + FND combination were significantly more effective than the CXL monotherapy, one and 2 weeks after therapy and especially in regressing lymphatic vessels. Furthermore, the combination therapy induced significantly less immune cell recruitment compared to the monotherapies. All three methods were safe to use in regards of corneal integrity. CONCLUSIONS A combination of FND and CXL led to regression of pathological corneal lymphatic and blood vessels and reduced the infiltration of immune cells into inflamed murine corneas. This approach offers a new effective, safe and clinically usable strategy to treat eyes with mature pathological blood vessels and even more so for lymphatic vessels, for example prior to high-risk corneal transplantation.
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Affiliation(s)
- Yanhong Hou
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
- Department of Ophthalmology, Fudan University Eye Ear Nose and Throat Hospital, Shanghai, China
| | - Wei Zhang
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
| | - Viet Nhat Hung Le
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
- Department of Ophthalmology, Hue College of Medicine and Pharmacy, Hue University, Ho Chi Minh City, Vietnam
| | - Shuya Deng
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
| | - Mert Mestanoglu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
| | - Gwen Musial
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Koln, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Koln, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Koln, Germany
- CECAD Cluster of Excellence, University of Cologne, Koln, Germany
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10
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Yam AO, Jakovija A, Gatt C, Chtanova T. Neutrophils under the microscope: neutrophil dynamics in infection, inflammation, and cancer revealed using intravital imaging. Front Immunol 2024; 15:1458035. [PMID: 39439807 PMCID: PMC11493610 DOI: 10.3389/fimmu.2024.1458035] [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: 07/01/2024] [Accepted: 09/13/2024] [Indexed: 10/25/2024] Open
Abstract
Neutrophils rapidly respond to inflammation resulting from infection, injury, and cancer. Intravital microscopy (IVM) has significantly advanced our understanding of neutrophil behavior, enabling real-time visualization of their migration, interactions with pathogens, and coordination of immune responses. This review delves into the insights provided by IVM studies on neutrophil dynamics in various inflammatory contexts. We also examine the dual role of neutrophils in tumor microenvironments, where they can either facilitate or hinder cancer progression. Finally, we highlight how computational modeling techniques, especially agent-based modeling, complement experimental data by elucidating neutrophil kinetics at the level of individual cells as well as their collective behavior. Understanding the role of neutrophils in health and disease is essential for developing new strategies for combating infection, inflammation and cancer.
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Affiliation(s)
- Andrew O. Yam
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia
- Immune Biotherapeutics Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s School of Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
- The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, NSW, Australia
| | - Arnolda Jakovija
- St Vincent’s School of Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Catherine Gatt
- St Vincent’s School of Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Tatyana Chtanova
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia
- St Vincent’s School of Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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11
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Viana IS, Di Filippo PA, Gobbi FP, Ribeiro RB, Carra GJU, Ribeiro LMF, Ribeiro LDS, Rocha MDCP, Canola PA. Cyanoacrylate Adhesives for Cutaneous Wound Closure. Animals (Basel) 2024; 14:2678. [PMID: 39335267 PMCID: PMC11428703 DOI: 10.3390/ani14182678] [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: 08/17/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Cyanoacrylate-based adhesives are widely used in wound closure, providing good cosmetic results and little discomfort. However, reports in the literature are found about negative effects that include the release of cytotoxic chemicals during biodegradation. In this study, we sought to evaluate and compare the effectiveness of four cyanoacrylate-based adhesives on the closure of skin incisions in Rattus norvegicus. The animals (n = 140) were divided into five groups of 28 animals each according to the wound closure technique: G1 and G2 (n-2-ethyl-cyanoacrylate); G3 (n-2-butyl-cyanoacrylate); G4 (n-2-octyl-cyanoacrylate); and G5 (5 nylon stitches). Midline incisions measuring 5.0 cm in length were created and closed using the different materials evaluated, and on D3, D7, D14, and D21, tensiometric and histopathological analyses were performed. Shorter wound closure and adhesion times were observed in G4 animals. At D3 and D7, G5 presented greater tensiometric resistance in the animals of G5, with a decrease in D14 and D21 compared to the other groups. On the other hand, the wounds of G3 and G4 were more resistant in D14 and D21, reaching maximum resistance values. Polymorphonuclear and mononuclear cells are more prevalent and more granulation tissue was observed in G5. The deposition of type III collagen was more evident in G5, whilst there was no difference in the amount of type I collagen in any of the groups treated with cyanoacrylate adhesives. Larger areas stained positive for VEGF-α in G2 and smaller areas in G4, with peaks at D7 and D14. In general, cyanoacrylate adhesives cause less intense inflammatory reactions, resulting in shorter healing times when compared to nylon sutures.
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Affiliation(s)
- Inácio Silva Viana
- Clinical and Animal Surgery Laboratory, Faculty of Agricultural and Veterinary Sciences, São Paulo State University "Júlio de Mesquita Filho", Jaboticabal 14884-900, São Paulo, Brazil
| | - Paula Alessandra Di Filippo
- Clinical and Animal Surgery Laboratory, Sciences and Agricultural Center Technologies, State University of the North Fluminense (UENF), Campos dos Goytacazes 28013-602, Rio de Janeiro, Brazil
| | - Francielli Pereira Gobbi
- Clinical and Animal Surgery Laboratory, Sciences and Agricultural Center Technologies, State University of the North Fluminense (UENF), Campos dos Goytacazes 28013-602, Rio de Janeiro, Brazil
| | - Rachel Bittencourt Ribeiro
- Pathology and Morphology Animal Laboratory, Sciences and Agricultural Center Technologies, State University of the North Fluminense (UENF), Campos dos Goytacazes 28013-602, Rio de Janeiro, Brazil
| | - Gabriel João Unger Carra
- Clinical and Animal Surgery Laboratory, Faculty of Agricultural and Veterinary Sciences, São Paulo State University "Júlio de Mesquita Filho", Jaboticabal 14884-900, São Paulo, Brazil
| | - Luiza Maria Feitosa Ribeiro
- Clinical and Animal Surgery Laboratory, Sciences and Agricultural Center Technologies, State University of the North Fluminense (UENF), Campos dos Goytacazes 28013-602, Rio de Janeiro, Brazil
| | - Lara de Souza Ribeiro
- Pathology and Morphology Animal Laboratory, Sciences and Agricultural Center Technologies, State University of the North Fluminense (UENF), Campos dos Goytacazes 28013-602, Rio de Janeiro, Brazil
| | - Michelle do Carmo Pereira Rocha
- Clinical and Animal Surgery Laboratory, Faculty of Agricultural and Veterinary Sciences, São Paulo State University "Júlio de Mesquita Filho", Jaboticabal 14884-900, São Paulo, Brazil
| | - Paulo Aléscio Canola
- Clinical and Animal Surgery Laboratory, Faculty of Agricultural and Veterinary Sciences, São Paulo State University "Júlio de Mesquita Filho", Jaboticabal 14884-900, São Paulo, Brazil
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12
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Goumenaki P, Günther S, Kikhi K, Looso M, Marín-Juez R, Stainier DYR. The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration. NATURE CARDIOVASCULAR RESEARCH 2024; 3:1158-1176. [PMID: 39271818 PMCID: PMC11399109 DOI: 10.1038/s44161-024-00538-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 08/06/2024] [Indexed: 09/15/2024]
Abstract
The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88-/- ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.
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Affiliation(s)
- Pinelopi Goumenaki
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Stefan Günther
- DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Khrievono Kikhi
- Flow Cytometry Service Group, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Mario Looso
- DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
- Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Rubén Marín-Juez
- Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montreal, Quebec, Canada
- Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec, Canada
| | - Didier Y R Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
- DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, Bad Nauheim, Germany.
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.
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13
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Bergersen KV, Kavvathas B, Ford BD, Wilson EH. Toxoplasma infection induces an aged neutrophil population in the CNS that is associated with neuronal protection. J Neuroinflammation 2024; 21:189. [PMID: 39095837 PMCID: PMC11297776 DOI: 10.1186/s12974-024-03176-7] [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: 05/22/2024] [Accepted: 07/15/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood. MAIN TEXT This study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed "chronic brain neutrophils" (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies. CONCLUSIONS In conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.
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Affiliation(s)
- Kristina V Bergersen
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA
| | - Bill Kavvathas
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA
| | - Byron D Ford
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA
- College of Medicine, Howard University, Washington, D.C., USA
| | - Emma H Wilson
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA.
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14
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Shu LZ, Zhang XL, Ding YD, Lin H. From inflammation to bone formation: the intricate role of neutrophils in skeletal muscle injury and traumatic heterotopic ossification. Exp Mol Med 2024; 56:1523-1530. [PMID: 38945957 PMCID: PMC11297321 DOI: 10.1038/s12276-024-01270-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 03/22/2024] [Accepted: 04/16/2024] [Indexed: 07/02/2024] Open
Abstract
Neutrophils are emerging as an important player in skeletal muscle injury and repair. Neutrophils accumulate in injured tissue, thus releasing inflammatory factors, proteases and neutrophil extracellular traps (NETs) to clear muscle debris and pathogens when skeletal muscle is damaged. During the process of muscle repair, neutrophils can promote self-renewal and angiogenesis in satellite cells. When neutrophils are abnormally overactivated, neutrophils cause collagen deposition, functional impairment of satellite cells, and damage to the skeletal muscle vascular endothelium. Heterotopic ossification (HO) refers to abnormal bone formation in soft tissue. Skeletal muscle injury is one of the main causes of traumatic HO (tHO). Neutrophils play a pivotal role in activating BMPs and TGF-β signals, thus promoting the differentiation of mesenchymal stem cells and progenitor cells into osteoblasts or osteoclasts to facilitate HO. Furthermore, NETs are specifically localized at the site of HO, thereby accelerating the formation of HO. Additionally, the overactivation of neutrophils contributes to the disruption of immune homeostasis to trigger HO. An understanding of the diverse roles of neutrophils will not only provide more information on the pathogenesis of skeletal muscle injury for repair and HO but also provides a foundation for the development of more efficacious treatment modalities for HO.
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Affiliation(s)
- Lin-Zhen Shu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Xian-Lei Zhang
- Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Yi-Dan Ding
- Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Hui Lin
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China.
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15
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Han L, Song Y, Xiang W, Wang Z, Wang Y, Zhou X, Zhu DS, Guan Y. Fibrinogen deposition promotes neuroinflammation and fibrin-derived γ 377-395 peptide ameliorates neurological deficits after ischemic stroke. Int Immunopharmacol 2024; 131:111831. [PMID: 38489969 DOI: 10.1016/j.intimp.2024.111831] [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: 09/22/2023] [Revised: 02/09/2024] [Accepted: 03/06/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND Fibrin(ogen) deposition in the central nervous system (CNS) contributes to neuropathological injury; however, its role in ischemic stroke is unknown. In this study, we identified fibrinogen as a novel proinflammatory regulator of post-stroke neuroinflammation and revealed the neuro-protection effect of fibrin-derived γ377-395peptide in stroke. METHODS Fibrinogen depletion and fibrinogen-derived γ377-395peptide treatment were performed 2 h after establishing a permanent middle cerebral artery occlusion (pMCAO) model. The infarction volume, neurological score, fibrin(ogen) deposition, and inflammatory response were evaluated 24 h after occlusion. Both in vivo and in vitro studies were conducted to assess the therapeutic potential of the γ377-395peptide in blocking the interactions between fibrin(ogen) and neutrophils. RESULTS Fibrin(ogen) deposited in the infarct core promoted post-stroke inflammation and exacerbated neurological deficits in the acute phase after stroke onset. Reducing fibrinogen deposition resulted in a decrease in infarction volume, improved neurological scores, and reduced inflammation in the brain. Additionally, the presence of neutrophil accumulation near fibrin(ogen) deposits was observed in ischemic lesions, and the engagement of fibrin(ogen) by integrin receptor αMβ2 promoted neutrophil activation and post-stroke inflammation. Finally, inhibiting fibrin(ogen)-mediated neutrophil activation using a fibrinogen-derived γ377-395peptide significantly attenuated neurological deficits. CONCLUSIONS Fibrin(ogen) is a crucial regulator of post-stroke inflammation and contributes to secondary brain injury. The inflammation induced by fibrin(ogen) is primarily driven by neutrophils during acute ischemic stroke and can be ameliorated using the fibrin-derived γ377-395peptide. Targeting the fibrin(ogen)-mediated neuropathological process represents a promising approach for neuroprotective therapy after stroke while preserving its beneficial coagulation function.
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Affiliation(s)
- Lu Han
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yaying Song
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Weiwei Xiang
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Ze Wang
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yishu Wang
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Xiajun Zhou
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - De-Sheng Zhu
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Department of Neurology, Baoshan Branch, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200444, China.
| | - Yangtai Guan
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
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16
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Bui TM, Yalom LK, Ning E, Urbanczyk JM, Ren X, Herrnreiter CJ, Disario JA, Wray B, Schipma MJ, Velichko YS, Sullivan DP, Abe K, Lauberth SM, Yang GY, Dulai PS, Hanauer SB, Sumagin R. Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer. J Clin Invest 2024; 134:e174545. [PMID: 38329810 PMCID: PMC10977994 DOI: 10.1172/jci174545] [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: 08/04/2023] [Accepted: 02/06/2024] [Indexed: 02/10/2024] Open
Abstract
Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during the transition from inflammatory ulceration to CRC we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their proximity to peripheral blood, inflamed colon, and tumors. In silico pathway overrepresentation analysis, protein-network mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA data set and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in patients with UC. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings demonstrate a niche-directed PMN functional specialization and identify TAN contributions to tumor vascularization, delineating what we believe to be a new therapeutic framework for CRC treatment focused on TAN angiogenic properties.
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Affiliation(s)
- Triet M. Bui
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lenore K. Yalom
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Edward Ning
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jessica M. Urbanczyk
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Xingsheng Ren
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Caroline J. Herrnreiter
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jackson A. Disario
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Brian Wray
- Quantitative Data Science Core, Lurie Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Matthew J. Schipma
- Quantitative Data Science Core, Lurie Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yuri S. Velichko
- Department of Radiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - David P. Sullivan
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Kouki Abe
- Simpson Querrey Institute for Epigenetics and Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Shannon M. Lauberth
- Simpson Querrey Institute for Epigenetics and Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Parambir S. Dulai
- Department of Medicine, Gastroenterology and Hepatology, Northwestern Memorial Hospital, Chicago, Illinois, USA
| | - Stephen B. Hanauer
- Department of Medicine, Gastroenterology and Hepatology, Northwestern Memorial Hospital, Chicago, Illinois, USA
| | - Ronen Sumagin
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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17
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Efromson J, Ferrero G, Bègue A, Doman TJJ, Dugo C, Barker A, Saliu V, Reamey P, Kim K, Harfouche M, Yoder JA. Automated, high-throughput quantification of EGFP-expressing neutrophils in zebrafish by machine learning and a highly-parallelized microscope. PLoS One 2023; 18:e0295711. [PMID: 38060605 PMCID: PMC10703246 DOI: 10.1371/journal.pone.0295711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/26/2023] [Indexed: 12/18/2023] Open
Abstract
Normal development of the immune system is essential for overall health and disease resistance. Bony fish, such as the zebrafish (Danio rerio), possess all the major immune cell lineages as mammals and can be employed to model human host response to immune challenge. Zebrafish neutrophils, for example, are present in the transparent larvae as early as 48 hours post fertilization and have been examined in numerous infection and immunotoxicology reports. One significant advantage of the zebrafish model is the ability to affordably generate high numbers of individual larvae that can be arrayed in multi-well plates for high throughput genetic and chemical exposure screens. However, traditional workflows for imaging individual larvae have been limited to low-throughput studies using traditional microscopes and manual analyses. Using a newly developed, parallelized microscope, the Multi-Camera Array Microscope (MCAM™), we have optimized a rapid, high-resolution algorithmic method to count fluorescently labeled cells in zebrafish larvae in vivo. Using transgenic zebrafish larvae, in which neutrophils express EGFP, we captured 18 gigapixels of images across a full 96-well plate, in 75 seconds, and processed the resulting datastream, counting individual fluorescent neutrophils in all individual larvae in 5 minutes. This automation is facilitated by a machine learning segmentation algorithm that defines the most in-focus view of each larva in each well after which pixel intensity thresholding and blob detection are employed to locate and count fluorescent cells. We validated this method by comparing algorithmic neutrophil counts to manual counts in larvae subjected to changes in neutrophil numbers, demonstrating the utility of this approach for high-throughput genetic and chemical screens where a change in neutrophil number is an endpoint metric. Using the MCAM™ we have been able to, within minutes, acquire both enough data to create an automated algorithm and execute a biological experiment with statistical significance. Finally, we present this open-source software package which allows the user to train and evaluate a custom machine learning segmentation model and use it to localize zebrafish and analyze cell counts within the segmented region of interest. This software can be modified as needed for studies involving other zebrafish cell lineages using different transgenic reporter lines and can also be adapted for studies using other amenable model species.
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Affiliation(s)
- John Efromson
- Ramona Optics Inc., Durham, NC, United States of America
| | - Giuliano Ferrero
- Department of Molecular Biological Sciences, North Carolina State University, Raleigh, NC, United States of America
| | - Aurélien Bègue
- Ramona Optics Inc., Durham, NC, United States of America
| | | | - Clay Dugo
- Ramona Optics Inc., Durham, NC, United States of America
| | - Andi Barker
- Department of Molecular Biological Sciences, North Carolina State University, Raleigh, NC, United States of America
| | - Veton Saliu
- Ramona Optics Inc., Durham, NC, United States of America
| | - Paul Reamey
- Ramona Optics Inc., Durham, NC, United States of America
| | - Kanghyun Kim
- Department of Biomedical Engineering, Duke University, Durham, NC, United States of America
| | - Mark Harfouche
- Ramona Optics Inc., Durham, NC, United States of America
| | - Jeffrey A. Yoder
- Department of Molecular Biological Sciences, North Carolina State University, Raleigh, NC, United States of America
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18
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Shadmani A, Ercal O, Uzun S, Swarup A, Wu AY. Regenerated Corneal Epithelium Expresses More βIII-Tubulin After Chemical Injuries Compared to Mechanical Injuries. Transl Vis Sci Technol 2023; 12:12. [PMID: 38085248 PMCID: PMC10720757 DOI: 10.1167/tvst.12.12.12] [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: 06/17/2023] [Accepted: 10/31/2023] [Indexed: 12/17/2023] Open
Abstract
Purpose Defining the regenerative response following various types of corneal chemical and mechanical injuries is important for understanding the pathophysiology of the injury and evaluating the effectiveness of the therapies. This study characterizes corneal epithelial healing in a murine chemical and mechanical injury model. Methods Four groups of 10 mice each received complete corneolimbal injuries by AlgerBrush, AlgerBrush/thermal, NaOH (0.5 N), or ethanol. Slit-lamp and optical coherence tomography examinations were performed daily for 14 days. Corneal opacity (CO) and neovascularization (NV) were evaluated. The origin of the regenerated epithelium was illustrated by anti-cytokeratin 12 (K12) and anti-K13. The height of regenerated corneal epithelium and intraepithelial free nerve endings (FNEs) stained with anti-βIII-tubulin were measured. The amount of fibrosis was measured by anti-α-smooth muscle actin (α-SMA) monoclonal antibody in the different groups. Statistical analysis was performed by ANOVA and t-test. Results Corneal opacity and neovascularization were markedly higher in the NaOH and AlgerBrush/thermal groups. Molecular studies revealed the following: Regenerated corneal epithelium thickness was less than normal in all groups, the AlgerBrush group had the shortest height of the regenerated epithelium, βIII-tubulin was expressed in the entire height of corneal epithelium in all groups except in the AlgerBrush group, and K12 was replaced by K13 in all groups. Conclusions Corneal wound healing is more effective following chemical injuries in terms of epithelial thickness. Inflammation may play an important role in the outcome. Translational Relevance Inflammation following different injuries may be redirected to be more effective in corneal regeneration and clarity.
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Affiliation(s)
- Athar Shadmani
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ozlem Ercal
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA
| | - Salih Uzun
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aditi Swarup
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA
| | - Albert Y. Wu
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA
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19
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Graca FA, Minden-Birkenmaier BA, Stephan A, Demontis F, Labelle M. Signaling roles of platelets in skeletal muscle regeneration. Bioessays 2023; 45:e2300134. [PMID: 37712935 PMCID: PMC10840841 DOI: 10.1002/bies.202300134] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/30/2023] [Accepted: 09/06/2023] [Indexed: 09/16/2023]
Abstract
Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α-granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet-derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet-secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, and impeding this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo-angiogenesis and the growth of newly formed myofibers, and reduces post-injury muscle force production. Platelets also contribute to the recruitment of pro-regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease.
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Affiliation(s)
- Flavia A. Graca
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | | | - Anna Stephan
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Fabio Demontis
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Myriam Labelle
- Department of Oncology, Division of Molecular Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
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20
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Deliyanti D, Suphapimol V, Ang P, Tang X, Jayasimhan A, Wilkinson-Berka JL. Early Depletion of Neutrophils Reduces Retinal Inflammation and Neovascularization in Mice with Oxygen-Induced Retinopathy. Int J Mol Sci 2023; 24:15680. [PMID: 37958664 PMCID: PMC10648252 DOI: 10.3390/ijms242115680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal vaso-obliteration in phase I, followed by retinal neovascularization in phase II. As neutrophils are acute responders to tissue damage, we evaluated whether neutrophil depletion with an anti-Ly6G mAb administered in phase I OIR influenced retinal inflammation and vascular injury. Neutrophils were measured in blood and spleen via flow cytometry, and myeloperoxidase, an indicator of neutrophil activity, was evaluated in the retina using Western blotting. Retinal vasculopathy was assessed by quantitating vaso-obliteration, neovascularization, vascular leakage, and VEGF levels. The inflammatory factors, TNF, MCP-1, and ICAM-1 were measured in retina. In the OIR controls, neutrophils were increased in the blood and spleen in phase I but not phase II OIR. In OIR, the anti-Ly6G mAb reduced neutrophils in the blood and spleen, and myeloperoxidase, inflammation, and vasculopathy in the retina. Our findings revealed that the early rise in neutrophils in OIR primes the retina for an inflammatory and angiogenic response that promotes severe damage to the retinal vasculature.
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Affiliation(s)
| | | | | | | | | | - Jennifer L. Wilkinson-Berka
- Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010, Australia; (D.D.); (V.S.); (P.A.); (X.T.); (A.J.)
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21
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Lörchner H, Cañes Esteve L, Góes ME, Harzenetter R, Brachmann N, Gajawada P, Günther S, Doll N, Pöling J, Braun T. Neutrophils for Revascularization Require Activation of CCR6 and CCL20 by TNFα. Circ Res 2023; 133:592-610. [PMID: 37641931 DOI: 10.1161/circresaha.123.323071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Activation of immune-inflammatory pathways involving TNFα (tumor necrosis factor alpha) signaling is critical for revascularization and peripheral muscle tissue repair after ischemic injury. However, mechanisms of TNFα-driven inflammatory cascades directing recruitment of proangiogenic immune cells to sites of ischemia are unknown. METHODS Muscle tissue revascularization after permanent femoral artery ligation was monitored in mutant mice by laser Doppler imaging and light sheet fluorescence microscopy. TNFα-mediated signaling and the role of the CCL20 (C-C motif chemokine ligand 20)-CCR6 (C-C chemokine receptor 6) axis for formation of new vessels was studied in vitro and in vivo using bone marrow transplantation, flow cytometry, as well as biochemical and molecular biological techniques. RESULTS TNFα-mediated activation of TNFR (tumor necrosis factor receptor) 1 but not TNFR2 was found to be required for postischemic muscle tissue revascularization. Bone marrow-derived CCR6+ neutrophil granulocytes were identified as a previously undescribed TNFα-induced population of proangiogenic neutrophils, characterized by increased expression of VEGFA (vascular endothelial growth factor A). Mechanistically, postischemic activation of TNFR1 induced expression of the CCL20 in vascular cells and promoted translocation of the CCL20 receptor CCR6 to the cell surface of neutrophils, essentially conditioning VEGFA-expressing proangiogenic neutrophils for CCL20-dependent recruitment to sites of ischemia. Moreover, impaired revascularization of ischemic peripheral muscle tissue in diabetic mice was associated with reduced numbers of proangiogenic neutrophils and diminished CCL20 expression. Administration of recombinant CCL20 enhanced recruitment of proangiogenic neutrophils and improved revascularization of diabetic ischemic skeletal muscles, which was sustained by sequential treatment with fluvastatin. CONCLUSIONS We demonstrate that site-specific activation of the CCL20-CCR6 axis via TNFα recruits proangiogenic VEGFA-expressing neutrophils to sites of ischemic injury for initiation of muscle tissue revascularization. The findings provide an attractive option for tissue revascularization, particularly under diabetic conditions.
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Affiliation(s)
- Holger Lörchner
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
- German Centre for Cardiovascular Research (DZHK), Frankfurt am Main, Germany (H.L., J.P.)
| | - Laia Cañes Esteve
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
| | - Maria Elisa Góes
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
| | - Roxanne Harzenetter
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
| | - Nathalie Brachmann
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
| | - Praveen Gajawada
- Department of Cardiac Surgery, Kerckhoff Heart Center, Bad Nauheim, Germany (P.G.)
| | - Stefan Günther
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
| | - Nicolas Doll
- Schüchtermann-Klinik, Bad Rothenfelde, Germany (N.D., J.P.)
| | - Jochen Pöling
- Schüchtermann-Klinik, Bad Rothenfelde, Germany (N.D., J.P.)
- German Centre for Cardiovascular Research (DZHK), Frankfurt am Main, Germany (H.L., J.P.)
| | - Thomas Braun
- Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (H.L., L.C.E., M.E.G., R.H., N.B., S.G., T.B.)
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22
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Castillo-Casas JM, Caño-Carrillo S, Sánchez-Fernández C, Franco D, Lozano-Velasco E. Comparative Analysis of Heart Regeneration: Searching for the Key to Heal the Heart-Part II: Molecular Mechanisms of Cardiac Regeneration. J Cardiovasc Dev Dis 2023; 10:357. [PMID: 37754786 PMCID: PMC10531542 DOI: 10.3390/jcdd10090357] [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: 07/25/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/28/2023] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide, among which ischemic heart disease is the most representative. Myocardial infarction results from occlusion of a coronary artery, which leads to an insufficient blood supply to the myocardium. As it is well known, the massive loss of cardiomyocytes cannot be solved due the limited regenerative ability of the adult mammalian hearts. In contrast, some lower vertebrate species can regenerate the heart after an injury; their study has disclosed some of the involved cell types, molecular mechanisms and signaling pathways during the regenerative process. In this 'two parts' review, we discuss the current state-of-the-art of the main response to achieve heart regeneration, where several processes are involved and essential for cardiac regeneration.
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Affiliation(s)
- Juan Manuel Castillo-Casas
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
| | - Sheila Caño-Carrillo
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
| | - Cristina Sánchez-Fernández
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
- Medina Foundation, 18007 Granada, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
- Medina Foundation, 18007 Granada, Spain
| | - Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
- Medina Foundation, 18007 Granada, Spain
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23
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Efromson J, Ferrero G, Bègue A, Doman TJJ, Dugo C, Barker A, Saliu V, Reamey P, Kim K, Harfouche M, Yoder JA. Automated, high-throughput quantification of EGFP-expressing neutrophils in zebrafish by machine learning and a highly-parallelized microscope. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.16.553550. [PMID: 37645798 PMCID: PMC10462042 DOI: 10.1101/2023.08.16.553550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Normal development of the immune system is essential for overall health and disease resistance. Bony fish, such as the zebrafish (Danio rerio), possess all the major immune cell lineages as mammals and can be employed to model human host response to immune challenge. Zebrafish neutrophils, for example, are present in the transparent larvae as early as 48 hours post fertilization and have been examined in numerous infection and immunotoxicology reports. One significant advantage of the zebrafish model is the ability to affordably generate high numbers of individual larvae that can be arrayed in multi-well plates for high throughput genetic and chemical exposure screens. However, traditional workflows for imaging individual larvae have been limited to low-throughput studies using traditional microscopes and manual analyses. Using a newly developed, parallelized microscope, the Multi-Camera Array Microscope (MCAM™), we have optimized a rapid, high-resolution algorithmic method to count fluorescently labeled cells in zebrafish larvae in vivo. Using transgenic zebrafish larvae, in which neutrophils express EGFP, we captured 18 gigapixels of images across a full 96-well plate, in 75 seconds, and processed the resulting datastream, counting individual fluorescent neutrophils in all individual larvae in 5 minutes. This automation is facilitated by a machine learning segmentation algorithm that defines the most in-focus view of each larva in each well after which pixel intensity thresholding and blob detection are employed to locate and count fluorescent cells. We validated this method by comparing algorithmic neutrophil counts to manual counts in larvae subjected to changes in neutrophil numbers, demonstrating the utility of this approach for high-throughput genetic and chemical screens where a change in neutrophil number is an endpoint metric. Using the MCAM™ we have been able to, within minutes, acquire both enough data to create an automated algorithm and execute a biological experiment with statistical significance. Finally, we present this open-source software package which allows the user to train and evaluate a custom machine learning segmentation model and use it to localize zebrafish and analyze cell counts within the segmented region of interest. This software can be modified as needed for studies involving other zebrafish cell lineages using different transgenic reporter lines and can also be adapted for studies using other amenable model species.
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Affiliation(s)
| | - Giuliano Ferrero
- Department of Molecular Biological Sciences, North Carolina State University, Raleigh, NC
| | | | | | | | - Andi Barker
- Department of Molecular Biological Sciences, North Carolina State University, Raleigh, NC
| | | | | | - Kanghyun Kim
- Department of Biomedical Engineering, Duke University, Durham, NC
| | | | - Jeffrey A. Yoder
- Department of Molecular Biological Sciences, North Carolina State University, Raleigh, NC
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24
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Lu X, Chen Z, Lu J, Watsky M. Effects of Topical 1,25 and 24,25 Vitamin D on Diabetic, Vitamin D Deficient and Vitamin D Receptor Knockout Mouse Corneal Wound Healing. Biomolecules 2023; 13:1065. [PMID: 37509101 PMCID: PMC10377579 DOI: 10.3390/biom13071065] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
Delayed or prolonged corneal wound healing and non-healing corneas put patients at risk for ocular surface infections and subsequent stromal opacification, resulting in discomfort or visual loss. It is important to enhance corneal wound healing efficiency and quality. Vitamin D (Vit D) is both a hormone and a vitamin, and its insufficiency has been linked to immune disorders and diabetes. For this study, wound healing and recruitment of CD45+ cells into the wound area of normoglycemic and diabetic mice were examined following corneal epithelial debridement and treatment with 1,25-dihyroxyvitamin D (1,25 Vit D) or 24,25-dihydroxyvitamin D (24,25 Vit D). Treatment with topical 1,25-dihyroxyvitamin D (1,25 Vit D) resulted in significantly increased corneal wound healing rates of normoglycemic, diabetic and diabetic Vit D deficient mice. Furthermore, 24,25-dihydroxyvitamin D (24,25 Vit D) significantly increased corneal wound healing of diabetic Vit D deficient and Vit D receptor knockout (VDR KO) mice. In addition, CD45+ cell numbers were reduced in diabetic and VDR KO mouse corneas compared to normoglycemic mice, and 24,25 Vit D increased the recruitment of CD45+ cells to diabetic mouse corneas after epithelial debridement. CD45+ cells were found to infiltrate into the corneal basal epithelial layer after corneal epithelial debridement. Our data indicate that topical Vit D promotes corneal wound healing and further supports previous work that the Vit D corneal wound healing effect is not totally VDR-dependent.
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Affiliation(s)
| | | | | | - Mitchell Watsky
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
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25
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Hou F, Zhang Q, Zhang W, Xiang C, Zhang G, Wang L, Zheng Z, Guo Y, Chen Z, Hernesniemi J, Feng G, Gu J. A correlation and prediction study of the poor prognosis of high-grade aneurysmal subarachnoid hemorrhage from the neutrophil percentage to albumin ratio. Clin Neurol Neurosurg 2023; 230:107788. [PMID: 37229954 DOI: 10.1016/j.clineuro.2023.107788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/30/2023] [Accepted: 05/13/2023] [Indexed: 05/27/2023]
Abstract
OBJECTIVE Inflammatory response and nutritional status play crucial roles in patients with aneurysmal subarachnoid hemorrhage (aSAH). This study mainly investigated the correlation between neutrophil percentage to albumin ratio (NPAR) and clinical prognosis in aSAH patients with high-grade Hunt-Hess and its predictive model. METHODS A retrospective analysis was conducted based on 806 patients with aneurysmal subarachnoid hemorrhage who were admitted to the studied hospital from January 2017 to December 2021. Modified Fisher grade and Hunt-Hess grade were obtained according to their status at admission and hematological parameters within 48 h after hemorrhage. Univariate and multivariate logistic regression analysis were conducted to evaluate the relationship between NPAR and the clinical prognosis of patients with aSAH. And propensity matching analysis of patients with aSAH in the severe group. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off value of NPAR at admission to predict prognosis and its sensitivity and specificity. The nomogram diagram and Calibration curve were further used to examine the prediction model. RESULTS According to the mRS score at discharge, 184 (22.83 %) cases were classified as having poor outcomes (mRS > 2). Through multivariate logistic regression analysis, it was found that the Modified Fisher grade at admission, Hunt-Hess grade, eosinophils, neutrophil to lymphocyte ratio (NLR), and NPAR were independent risk factors for poor outcome in patients with aSAH (p < 0.05). The NPAR of aSAH patients with poor outcomes in the high-grade group was significantly higher than that in the low-grade group. The optimal cut-off value for NPAR was 21.90, the area under the ROC curve was 0.780 (95 % CI 0.700 - 0.861, p < 0.001). The Calibration curves show that the predicted probability of the drawn nomogram is overall consistent with the actual probability. (Mean absolute error = 0.031) CONCLUSION: The NPAR value of patients with aSAH at admission is significantly correlated with Hunt-Hess grade in a positive manner, namely, the higher the Hunt-Hess grade, the higher the NPAR value, and the worse the prognosis. Findings indicate that early NPAR value can be used as a feasible biomarker to predict the clinical prognosis of patients with aSAH.
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Affiliation(s)
- Fandi Hou
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Qingqing Zhang
- Department of Neurosurgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China; Henan University, Kaifeng, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Wanwan Zhang
- Department of Neurosurgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China; Henan University, Kaifeng, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Chao Xiang
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Gaoqi Zhang
- Department of Neurosurgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China; Henan University, Kaifeng, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Lintao Wang
- Henan University, Kaifeng, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Zhanqiang Zheng
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Yong Guo
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Zhongcan Chen
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Juha Hernesniemi
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Guang Feng
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China
| | - Jianjun Gu
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, China; Department of Neurosurgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China.
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Steffan BN, Calise D, Park SC, Niu M, Yang J, Hammock BD, Jones M, Steele C, Keller NP. Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis. Front Immunol 2023; 14:1173544. [PMID: 37435068 PMCID: PMC10331294 DOI: 10.3389/fimmu.2023.1173544] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/01/2023] [Indexed: 07/13/2023] Open
Abstract
Background Aspergillus fumigatus is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised populations. The severity of IPA is dependent on both host- and pathogen-derived signaling molecules that mediate host immunity and fungal growth. Oxylipins are bioactive oxygenated fatty acids known to influence host immune response and Aspergillus developmental programs. Aspergillus synthesizes 8-HODE and 5,8-diHODE that have structural similarities to 9-HODE and 13-HODE, which are known ligands of the host G-protein-coupled receptor G2A (GPR132). Materials and methods Oxylipins were extracted from infected lung tissue to assess fungal oxylipin production and the Pathhunter β-arrestin assay was used to assess agonist and antagonist activity by fungal oxylipins on G2A. An immunocompetent model of A. fumigatus infection was used to assess changes in survival and immune responses for G2A-/- mice. Results Here we report that Aspergillus oxylipins are produced in lung tissue of infected mice and in vitro ligand assays suggest 8-HODE is a G2A agonist and 5,8-diHODE is a partial antagonist. To address the hypothesis that G2A could be involved in the progression of IPA, we assessed the response of G2A-/- mice to A. fumigatus infection. G2A-/- mice showed a survival advantage over wild-type mice; this was accompanied by increased recruitment of G2A-/- neutrophils and increased levels of inflammatory markers in A. fumigatus-infected lungs. Conclusions We conclude that G2A suppresses host inflammatory responses to Aspergillus fumigatus although it remains unclear if fungal oxylipins are involved in G2A activities.
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Affiliation(s)
- Breanne N. Steffan
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
| | - Dante Calise
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
| | - Sung Chul Park
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
| | - Mengyao Niu
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
| | - Jun Yang
- Department of Entomology, University of California-Davis, Davis, CA, United States
| | - Bruce D. Hammock
- Department of Entomology, University of California-Davis, Davis, CA, United States
| | - MaryJane Jones
- Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA, United States
| | - Chad Steele
- Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA, United States
| | - Nancy P. Keller
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
- Department of Plant Pathology, University of Wisconsin-Madison, Madison, WI, United States
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27
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Sousa AB, Barbosa JN. The Role of Neutrophils in Biomaterial-Based Tissue Repair-Shifting Paradigms. J Funct Biomater 2023; 14:327. [PMID: 37367291 DOI: 10.3390/jfb14060327] [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: 05/18/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
Tissue engineering and regenerative medicine are pursuing clinical valid solutions to repair and restore function of damaged tissues or organs. This can be achieved in different ways, either by promoting endogenous tissue repair or by using biomaterials or medical devices to replace damaged tissues. The understanding of the interactions of the immune system with biomaterials and how immune cells participate in the process of wound healing are critical for the development of successful solutions. Until recently, it was thought that neutrophils participate only in the initial steps of an acute inflammatory response with the role of eliminating pathogenic agents. However, the appreciation that upon activation the longevity of neutrophils is highly increased and the fact that neutrophils are highly plastic cells and can polarize into different phenotypes led to the discovery of new and important actions of neutrophils. In this review, we focus on the roles of neutrophils in the resolution of the inflammatory response, in biomaterial-tissue integration and in the subsequent tissue repair/regeneration. We also discuss the potential of neutrophils for biomaterial-based immunomodulation.
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Affiliation(s)
- Ana Beatriz Sousa
- i3S-Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Judite N Barbosa
- i3S-Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
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Jakovija A, Chtanova T. Skin immunity in wound healing and cancer. Front Immunol 2023; 14:1060258. [PMID: 37398649 PMCID: PMC10312005 DOI: 10.3389/fimmu.2023.1060258] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 05/24/2023] [Indexed: 07/04/2023] Open
Abstract
The skin is the body's largest organ. It serves as a barrier to pathogen entry and the first site of immune defense. In the event of a skin injury, a cascade of events including inflammation, new tissue formation and tissue remodeling contributes to wound repair. Skin-resident and recruited immune cells work together with non-immune cells to clear invading pathogens and debris, and guide the regeneration of damaged host tissues. Disruption to the wound repair process can lead to chronic inflammation and non-healing wounds. This, in turn, can promote skin tumorigenesis. Tumors appropriate the wound healing response as a way of enhancing their survival and growth. Here we review the role of resident and skin-infiltrating immune cells in wound repair and discuss their functions in regulating both inflammation and development of skin cancers.
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Affiliation(s)
- Arnolda Jakovija
- Immunity Theme, Garvan Institute of Medical Research, Sydney, Australia
- St. Vincent’s School of Medicine, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Tatyana Chtanova
- Immunity Theme, Garvan Institute of Medical Research, Sydney, Australia
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia
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Graca FA, Stephan A, Minden-Birkenmaier BA, Shirinifard A, Wang YD, Demontis F, Labelle M. Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles. Nat Commun 2023; 14:2900. [PMID: 37217480 DOI: 10.1038/s41467-023-38624-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 05/09/2023] [Indexed: 05/24/2023] Open
Abstract
Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to muscle repair but whether platelets promote regeneration beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines is an early event necessary for muscle repair in mice. Platelet depletion reduces the levels of the platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase neutrophil infiltration to injured muscles is impaired whereas later inflammation is exacerbated. Consistent with this model, neutrophil infiltration to injured muscles is compromised in male mice with Cxcl7-knockout platelets. Moreover, neo-angiogenesis and the re-establishment of myofiber size and muscle strength occurs optimally in control mice post-injury but not in Cxcl7ko mice and in neutrophil-depleted mice. Altogether, these findings indicate that platelet-secreted CXCL7 promotes regeneration by recruiting neutrophils to injured muscles, and that this signaling axis could be utilized therapeutically to boost muscle regeneration.
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Affiliation(s)
- Flavia A Graca
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Anna Stephan
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Benjamin A Minden-Birkenmaier
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
- Department of Oncology, Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Abbas Shirinifard
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Yong-Dong Wang
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Fabio Demontis
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
| | - Myriam Labelle
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
- Department of Oncology, Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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Iwaniuk A, Jablonska E. Neutrophils in Health and Disease: From Receptor Sensing to Inflammasome Activation. Int J Mol Sci 2023; 24:ijms24076340. [PMID: 37047314 PMCID: PMC10094305 DOI: 10.3390/ijms24076340] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/22/2023] [Accepted: 03/25/2023] [Indexed: 03/30/2023] Open
Abstract
Neutrophils—polymorphonuclear cells (PMNs) are the cells of the initial immune response and make up the majority of leukocytes in the peripheral blood. After activation, these cells modify their functional status to meet the needs at the site of action or according to the agent causing injury. They receive signals from their surroundings and “plan” the course of the response in both temporal and spatial contexts. PMNs dispose of intracellular signaling pathways that allow them to perform a wide range of functions associated with the development of inflammatory processes. In addition to these cells, some protein complexes, known as inflammasomes, also have a special role in the development and maintenance of inflammation. These complexes participate in the proteolytic activation of key pro-inflammatory cytokines, such as IL-1β and IL-18. In recent years, there has been significant progress in the understanding of the structure and molecular mechanisms behind the activation of inflammasomes and their participation in the pathogenesis of numerous diseases. The available reports focus primarily on macrophages and dendritic cells. According to the literature, the activation of inflammasomes in neutrophils and the associated death type—pyroptosis—is regulated in a different manner than in other cells. The present work is a review of the latest reports concerning the course of inflammasome activation and inflammatory cytokine secretion in response to pathogens in neutrophils, as well as the role of these mechanisms in the pathogenesis of selected diseases.
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Siwicki M, Kubes P. Neutrophils in host defense, healing, and hypersensitivity: Dynamic cells within a dynamic host. J Allergy Clin Immunol 2023; 151:634-655. [PMID: 36642653 DOI: 10.1016/j.jaci.2022.12.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 11/11/2022] [Accepted: 12/02/2022] [Indexed: 01/15/2023]
Abstract
Neutrophils are cells of the innate immune system that are extremely abundant in vivo and respond quickly to infection, injury, and inflammation. Their constant circulation throughout the body makes them some of the first responders to infection, and indeed they play a critical role in host defense against bacterial and fungal pathogens. It is now appreciated that neutrophils also play an important role in tissue healing after injury. Their short life cycle, rapid response kinetics, and vast numbers make neutrophils a highly dynamic and potentially extremely influential cell population. It has become clear that they are highly integrated with other cells of the immune system and can thus exert critical effects on the course of an inflammatory response; they can further impact tissue homeostasis and recovery after challenge. In this review, we discuss the fundamentals of neutrophils in host defense and healing; we explore the relationship between neutrophils and the dynamic host environment, including circadian cycles and the microbiome; we survey the field of neutrophils in asthma and allergy; and we consider the question of neutrophil heterogeneity-namely, whether there could be specific subsets of neutrophils that perform different functions in vivo.
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Affiliation(s)
- Marie Siwicki
- Immunology Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Paul Kubes
- Immunology Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
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Wesdorp MA, Schwab A, Bektas EI, Narcisi R, Eglin D, Stoddart MJ, Van Osch GJ, D'Este M. A culture model to analyze the acute biomaterial-dependent reaction of human primary neutrophils in vitro. Bioact Mater 2023; 20:627-637. [PMID: 35846845 PMCID: PMC9256821 DOI: 10.1016/j.bioactmat.2022.05.036] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 05/08/2022] [Accepted: 05/28/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Marinus A. Wesdorp
- AO Research Institute Davos, AO Foundation, Davos Platz, Switzerland
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Andrea Schwab
- AO Research Institute Davos, AO Foundation, Davos Platz, Switzerland
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
- Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Ezgi Irem Bektas
- AO Research Institute Davos, AO Foundation, Davos Platz, Switzerland
| | - Roberto Narcisi
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - David Eglin
- AO Research Institute Davos, AO Foundation, Davos Platz, Switzerland
- Mines Saint-Étienne, Univ Lyon, Univ Jean Monnet, INSERM, U1059 Sainbiose, Saint-Étienne, France
- Department of Biomaterials Science and Technology, University of Twente, Enschede, the Netherlands
| | | | - Gerjo J.V.M. Van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
- Department of Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
- Department of Biomechanical Engineering, Faculty of Mechanical, Maritime, and Materials Engineering, Delft University of Technology, the Netherlands
| | - Matteo D'Este
- AO Research Institute Davos, AO Foundation, Davos Platz, Switzerland
- Corresponding author. AO Research Institute Davos, Clavadelerstrasse 8, 7270 Davos Platz, Switzerland.
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Ross M, Kargl CK, Ferguson R, Gavin TP, Hellsten Y. Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators. Eur J Appl Physiol 2023:10.1007/s00421-022-05128-6. [PMID: 36715739 DOI: 10.1007/s00421-022-05128-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/25/2022] [Indexed: 01/31/2023]
Abstract
Exercise-induced skeletal muscle angiogenesis is a well-known physiological adaptation that occurs in humans in response to exercise training and can lead to endurance performance benefits, as well as improvements in cardiovascular and skeletal tissue health. An increase in capillary density in skeletal muscle improves diffusive oxygen exchange and waste extraction, and thus greater fatigue resistance, which has application to athletes but also to the general population. Exercise-induced angiogenesis can significantly contribute to improvements in cardiovascular and metabolic health, such as the increase in muscle glucose uptake, important for the prevention of diabetes. Recently, our understanding of the mechanisms by which angiogenesis occurs with exercise has grown substantially. This review will detail the biochemical, cellular and biomechanical signals for exercise-induced skeletal muscle angiogenesis, including recent work on extracellular vesicles and circulating angiogenic cells. In addition, the influence of age, sex, exercise intensity/duration, as well as recent observations with the use of blood flow restricted exercise, will also be discussed in detail. This review will provide academics and practitioners with mechanistic and applied evidence for optimising training interventions to promote physical performance through manipulating capillarisation in skeletal muscle.
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Affiliation(s)
- Mark Ross
- School of Energy, Geoscience, Infrastructure and Society, Heriot-Watt University, Edinburgh, Scotland, UK.
| | - Christopher K Kargl
- Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, USA.,Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, USA
| | - Richard Ferguson
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Timothy P Gavin
- Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, USA
| | - Ylva Hellsten
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
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Ding P, Wu J, Wu H, Sun C, Guo H, Lowe S, Yang P, Tian Y, Liu Y, Meng L, Zhao Q. Inflammation and nutritional status indicators as prognostic indicators for patients with locally advanced gastrointestinal stromal tumors treated with neoadjuvant imatinib. BMC Gastroenterol 2023; 23:23. [PMID: 36690935 PMCID: PMC9869595 DOI: 10.1186/s12876-023-02658-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Previous studies have confirmed that preoperative nutritional-inflammatory indicators can predict prognosis in various malignancies. However, to the best of our knowledge, no study has investigated the assessment of systemic inflammatory immunity index (SII) combined with prognostic nutritional index (PNI) scores to predict prognosis after neoadjuvant treatment with imatinib in locally advanced gastrointestinal stromal tumours (LA-GIST). The aim of this study was to evaluate the predictive value of pretreatment SII-PNI scores in predicting recurrence after neoadjuvant therapy with imatinib in patients with LA-GIST. METHODS We retrospectively analyzed 57 patients with LA-GIST who received imatinib neoadjuvant from January 2013 to March 2019. Patients were divided into recurrence and non-recurrence groups according to their follow-up status, and SII and PNI cut-offs were calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 544.6) and low PNI (≤ 47.2); score of 1, either high SII (≥ 544.6) or low PNI (≤ 47.2); score of 0, no high SII (≥ 544.6) nor low PNI (≤ 47.2). RESULTS All patients received imatinib neoadjuvant therapy for a median treatment period of 8.5 months (ranging from 3.2 to 12.6 months), with 8 patients (14.04%) and 49 patients (85.96%) developing recurrence and non-recurrence, respectively. Patients with a high SII-PNI score had a significantly worse recurrence-free survival time than those with a low SII-PNI score (P = 0.022, 0.046), and had a poorer pathological response (P = 0.014). Multivariate analysis demonstrated that the SII-PNI score was an independent prognostic factor for prediction of recurrence-free survival (P = 0.002). CONCLUSION The pre-treatment SII-PNI score can be used to predict the efficacy after neoadjuvant treatment with imatinib in patients with LA-GIST, which may be a promising predictor of recurrence-free survival time for patients.
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Affiliation(s)
- Ping’an Ding
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Jiaxiang Wu
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Haotian Wu
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Chenyu Sun
- grid.488798.20000 0004 7535 783XAMITA Health Saint Joseph Hospital Chicago, 2900 N. Lake Shore Drive, Chicago, IL 60657 USA
| | - Honghai Guo
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Scott Lowe
- grid.258405.e0000 0004 0539 5056College of Osteopathic Medicine, Kansas City University, 1750 Independence Ave, Kansas City, MO 64106 USA
| | - Peigang Yang
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Yuan Tian
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Yang Liu
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
| | - Lingjiao Meng
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China ,grid.452582.cResearch Center of the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 China
| | - Qun Zhao
- grid.452582.cThe Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011 Hebei China ,Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011 China
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SAITO S, KELEL M. Oral administration of Lacticaseibacillus casei ATCC393 promotes angiogenesis by enhancing neutrophil activity in a murine hind-limb ischemia model. BIOSCIENCE OF MICROBIOTA, FOOD AND HEALTH 2023; 42:94-99. [PMID: 36660599 PMCID: PMC9816049 DOI: 10.12938/bmfh.2022-038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/13/2022] [Indexed: 01/01/2023]
Abstract
Angiogenesis is a highly regulated biological event and requires the participation of neutrophils, which are innate immune cells, to initiate the systematic responses. Some strains of lactic acid bacteria (LAB) can be used for probiotics that provide functional modifications in our immune systems. Here, we show that oral administration of Lacticaseibacillus casei ATCC393 promoted inflammatory angiogenesis accompanied by enhanced neutrophil activity. Heat-killed L. casei (HK-LC) administration improved angiogenesis in a murine hind-limb ischemia (HLI) model. The recruitment and activity of neutrophils were enhanced by HK-LC administration under the HLI conditions. Our results provide novel evidence of an immunological contribution of LAB uptake in the prevention of or recovery from cardiovascular diseases.
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Affiliation(s)
- Suguru SAITO
- Institute of Biomedical Sciences (IBMS), Academia Sinica, 128
Academia Road, Section 2, Nankang, Taipei 115, Taiwan,Division of Virology, Department of Infection and Immunity,
Faculty of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi
329-0498, Japan,Department of Dentistry, Faculty of Medicine and Dentistry,
University of Alberta, Edmonton, Alberta T6G 2R7, Canada,*Corresponding author. Suguru Saito (E-mail: )
| | - Musin KELEL
- Institute of Biomedical Sciences (IBMS), Academia Sinica, 128
Academia Road, Section 2, Nankang, Taipei 115, Taiwan,Department of Biotechnology, College of Biological and
Chemical Engineering, Addis Ababa Science and Technology University, Addis Ababa,
Ethiopia
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Cao W, Yu H, Zhu S, Lei X, Li T, Ren F, Zhou N, Tang Q, Zu L, Xu S. Clinical significance of preoperative neutrophil‐lymphocyte ratio and platelet‐lymphocyte ratio in the prognosis of resected early‐stage patients with non‐small cell lung cancer: A meta‐analysis. Cancer Med 2022; 12:7065-7076. [PMID: 36480232 PMCID: PMC10067053 DOI: 10.1002/cam4.5505] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/06/2022] [Accepted: 11/20/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Poor prognosis is linked to peripheral blood levels of preoperative platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in many advanced cancers. Nevertheless, whether the correlation exists in resected early-stage cases with non-small cell lung cancer (NSCLC) stays controversial. Consequently, we performed a meta-analysis to explore the preoperative NLR and PLR's prognostic significance in early-stage patients with NSCLC undergoing curative surgery. METHODS Relevant studies that validated the link between preoperative NLR or PLR and survival results were found via the proceeding databases: PubMed, Embase, Cochrane Library, and Web of Science. The merged 95% confidence interval (CI) and hazard ratio (HR) was employed to validate the link between the NLR or PLR's index and overall survival (OS) and disease-free survival (DFS) in resected NSCLC cases. We used sensitivity and subgroup analyses to assess the studies' heterogeneity. RESULTS An overall of 21 studies were attributed to the meta-analysis. The findings indicated that great preoperative NLR was considerably correlated with poor DFS (HR = 1.58, 95% CI: 1.37-1.82, p < 0.001) and poor OS (HR = 1.51, 95% CI: 1.33-1.72, p < 0.001), respectively. Subgroup analyses were in line with the pooled findings. In aspect of PLR, raised PLR was indicative of inferior DFS (HR = 1.28, 95% CI: 1.04-1.58, p = 0.021) and OS (HR = 1.37, 95% CI: 1.18-1.60, p < 0.001). In the subgroup analyses between PLR and DFS, only subgroups with a sample size <300 (HR = 1.67, 95% CI: 1.15-2.43, p = 0.008) and TNM staging of mixed (I-II) (HR = 1.47, 95% CI: 1.04-2.07, p = 0.028) showed that the link between high PLR and poor DFS was significant. CONCLUSIONS Preoperative elevated NLR and PLR may act as prognostic biomarkers in resected early-stage NSCLC cases and are therefore valuable for guiding postoperative adjuvant treatment.
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Affiliation(s)
- Weibo Cao
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Haochuan Yu
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Shuai Zhu
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Xi Lei
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Tong Li
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Fan Ren
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Ning Zhou
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Quanying Tang
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Lingling Zu
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
| | - Song Xu
- Department of Lung Cancer Surgery Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin China
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Zhou L, Ren L, Yu W, Qi M, Yuan J, Wang W, Su X, Yin F, Deng M, Wang H, Long H, Zeng J, Yu J, Fan H, Wang Z. Construction and validation of a prediction model of extrahepatic metastasis for hepatocellular carcinoma based on common clinically available data. Front Oncol 2022; 12:961194. [PMID: 36465396 PMCID: PMC9709221 DOI: 10.3389/fonc.2022.961194] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 10/25/2022] [Indexed: 08/09/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the clinical characteristics and risk factors of patients with hepatocellular carcinoma (HCC) with extrahepatic metastases (EHM) and to establish an effective predictive nomogram. METHODS Clinical and pathological data from 607 patients with hepatocellular carcinoma admitted to the Affiliated Hospital of Qinghai University between 1 January 2015 and 31 May 2018 were documented, as well as demographics, clinical pathological characteristics, and tumor-related parameters to clarify clinical risk factors for HCC EHM. These risks were selected to build an R-based clinical prediction model. The predictive accuracy and discriminating ability of the model were determined by the concordance index (C-index) and the calibration curve. The results were validated with a bootstrap resample and 151 patients from 1 June 2018 to 31 December 2019 at the same facility. RESULTS In multivariate analysis, independent factors for EHM were neutrophils, prothrombin time, tumor number, and size, all of which were selected in the model. The C-index in the EHM prediction model was 0.672 and in the validation cohort was 0.694. In the training cohort and the validation cohort, the calibration curve for the probability of EHM showed good agreement between the nomogram prediction and the actual observation. CONCLUSION The extrahepatic metastasis prediction model of hepatocellular carcinoma constructed in this study has some evaluation capability.
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Affiliation(s)
- Liuxin Zhou
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
- Department of Hepatopancreatobiliary Surgery, The Chongqing University Fuling Hospital, Fuling, Chongqing, China
| | - Li Ren
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Wenhao Yu
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Mengjian Qi
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Jiaqi Yuan
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Wen Wang
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Xiaoxia Su
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Fengjiao Yin
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Manjun Deng
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Haijiu Wang
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Hongmu Long
- Department of Hepatopancreatobiliary Surgery, The Chongqing University Fuling Hospital, Fuling, Chongqing, China
| | - Jiangchao Zeng
- Department of Hepatopancreatobiliary Surgery, The Chongqing University Fuling Hospital, Fuling, Chongqing, China
| | - Jiajian Yu
- Department of Hepatopancreatobiliary Surgery, The Chongqing University Fuling Hospital, Fuling, Chongqing, China
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
| | - Zhixin Wang
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, Qinghai, China
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Harju N. Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells. Acta Ophthalmol 2022; 100 Suppl 273:3-59. [DOI: 10.1111/aos.15275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Niina Harju
- School of Pharmacy University of Eastern Finland Kuopio Finland
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Gao Z, Yu Y, Dai K, Zhang T, Ji L, Wang X, Wang J, Liu C. Engineering Neutrophil Immunomodulatory Hydrogels Promoted Angiogenesis. ACS APPLIED MATERIALS & INTERFACES 2022; 14:39746-39758. [PMID: 36006024 DOI: 10.1021/acsami.2c08600] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Timely restoration of blood supply following ischemia is critical to rescue damaged tissue. However, clinical efficacy is hampered by the inflammatory response after ischemia. Whether inflammation fine tunes the angiogenesis and the function of blood vessels via the heterogeneity of neutrophils remain poorly understood. Herein, the objective of this work is to incorporate the growth factors secreted by neutrophils into a porous gelatin methacrylate (GelMA) hydrogel, which subsequently is used as a novel regenerative scaffold with defined architecture for ischemia. We demonstrate that anti-inflammatory neutrophils (N2-polarized neutrophils) play an important role in promoting the migration of human umbilical vein endothelial cells (HUVECs) and formation of capillary-like networks in vitro. More importantly, vascular anastomosis can be achieved by modulating the neutrophils to N2 phenotype. In addition, N2-polarized composite hydrogel scaffolds can regulate inflammation, maintain the survival of exogenous cells, and promote angiogenesis in vivo. Notably, the composite hydrogel scaffolds promote neovascularization during exogenous introduction of endothelial cells by anastomosis. Taken together, this study highlights N2-polarized neutrophils composite hydrogels can achieve vascularization rapidly by regulating inflammation and promoting vascular anastomosis. This work lays the foundation for research into the treatment of ischemia and may inspire further research into novel treatment options.
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Affiliation(s)
- Zehua Gao
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Yuanman Yu
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Kai Dai
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Tingting Zhang
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Luli Ji
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Xuanlin Wang
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Jing Wang
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR China
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Neutrophils and Neutrophil Extracellular Traps in Cardiovascular Disease: An Overview and Potential Therapeutic Approaches. Biomedicines 2022; 10:biomedicines10081850. [PMID: 36009397 PMCID: PMC9405087 DOI: 10.3390/biomedicines10081850] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/18/2022] [Accepted: 07/23/2022] [Indexed: 11/17/2022] Open
Abstract
Recent advances in pharmacotherapy have markedly improved the prognosis of cardiovascular disease (CVD) but have not completely conquered it. Therapies targeting the NOD-like receptor family pyrin domain containing 3 inflammasome and its downstream cytokines have proven effective in the secondary prevention of cardiovascular events, suggesting that inflammation is a target for treating residual risk in CVD. Neutrophil-induced inflammation has long been recognized as important in the pathogenesis of CVD. Circadian rhythm-related and disease-specific microenvironment changes give rise to neutrophil diversity. Neutrophils are primed by various stimuli, such as chemokines, cytokines, and damage-related molecular patterns, and the activated neutrophils contribute to the inflammatory response in CVD through degranulation, phagocytosis, reactive oxygen species generation, and the release of neutrophil extracellular traps (NETs). In particular, NETs promote immunothrombosis through the interaction with vascular endothelial cells and platelets and are implicated in the development of various types of CVD, such as acute coronary syndrome, deep vein thrombosis, and heart failure. NETs are promising candidates for anti-inflammatory therapy in CVD, and their efficacy has already been demonstrated in various animal models of the disease; however, they have yet to be clinically applied in humans. This narrative review discusses the diversity and complexity of neutrophils in the trajectory of CVD, the therapeutic potential of targeting NETs, and the related clinical issues.
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Abstract
Chronic wounds are characterized by their inability to heal within an expected time frame and have emerged as an increasingly important clinical problem over the past several decades, owing to their increasing incidence and greater recognition of associated morbidity and socio-economic burden. Even up to a few years ago, the management of chronic wounds relied on standards of care that were outdated. However, the approach to these chronic conditions has improved, with better prevention, diagnosis and treatment. Such improvements are due to major advances in understanding of cellular and molecular aspects of basic science, in innovative and technological breakthroughs in treatment modalities from biomedical engineering, and in our ability to conduct well-controlled and reliable clinical research. The evidence-based approaches resulting from these advances have become the new standard of care. At the same time, these improvements are tempered by the recognition that persistent gaps exist in scientific knowledge of impaired healing and the ability of clinicians to reduce morbidity, loss of limb and mortality. Therefore, taking stock of what is known and what is needed to improve understanding of chronic wounds and their associated failure to heal is crucial to ensuring better treatments and outcomes.
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Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation. Prog Retin Eye Res 2022; 91:101105. [PMID: 35868985 DOI: 10.1016/j.preteyeres.2022.101105] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/29/2022]
Abstract
In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4+ T cells, can be inhibitory to corneal re-innervation. Finally, this review considers the bidirectional interactions between corneal immune cells and corneal nerves, and how leveraging this interaction could represent a potential therapeutic approach for corneal neuropathy.
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The Involvement of Neutrophils in the Pathophysiology and Treatment of Osteoarthritis. Biomedicines 2022; 10:biomedicines10071604. [PMID: 35884909 PMCID: PMC9313259 DOI: 10.3390/biomedicines10071604] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 06/29/2022] [Accepted: 07/01/2022] [Indexed: 12/14/2022] Open
Abstract
Osteoarthritis (OA) is a chronic disability that significantly impairs quality of life. OA is one of the most prevalent joint pathologies in the world, characterized by joint pain and stiffness due to the degeneration of articular cartilage and the remodeling of subchondral bone. OA pathogenesis is unique in that it involves simultaneous reparative and degradative mechanisms. Low-grade inflammation as opposed to high-grade allows for this coexistence. Previously, macrophages and T cells have been identified as playing major roles in the inflammation and destruction of OA joints, but recent studies have demonstrated that neutrophils also contribute to the pathogenesis. Neutrophils are the first immune cells to enter the synovium after joint injury, and neutrophilic activity is indispensably a requisite for the progression of OA. Neutrophils act through multiple mechanisms including tissue degeneration via neutrophil elastase (NE), osteophyte development, and the release of inflammatory cytokines and chemokines. As the actions of neutrophils in OA are discovered, the potential for novel therapeutic targets as well as diagnostic methods are revealed. The use of chondrogenic progenitor cells (CPCs), microRNAs, and exosomes are among the newest therapeutic advances in OA treatment, and this review reveals how they can be used to mitigate destructive neutrophil activity.
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Mawhinney M, Kulle A, Thanabalasuriar A. From infection to repair: Understanding the workings of our innate immune cells. WIREs Mech Dis 2022; 14:e1567. [PMID: 35674186 DOI: 10.1002/wsbm.1567] [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: 01/12/2022] [Revised: 04/13/2022] [Accepted: 05/04/2022] [Indexed: 11/06/2022]
Abstract
In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to "nonself" like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Martin Mawhinney
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Amelia Kulle
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Ajitha Thanabalasuriar
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.,Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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Azcona JA, Tang S, Berry E, Zhang FF, Garvey R, Falck JR, Schwartzman ML, Yi T, Jeitner TM, Guo AM. Neutrophil-Derived Myeloperoxidase and Hypochlorous Acid Critically Contribute to 20-Hydroxyeicosatetraenoic Acid Increases that Drive Postischemic Angiogenesis. J Pharmacol Exp Ther 2022; 381:204-216. [PMID: 35306474 PMCID: PMC9190235 DOI: 10.1124/jpet.121.001036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/08/2022] [Indexed: 03/08/2025] Open
Abstract
Compensatory angiogenesis is an important adaptation for recovery from critical ischemia. We recently identified 20-hydroxyeicosatetraenoic acid (20-HETE) as a novel contributor of ischemia-induced angiogenesis. However, the precise mechanisms by which ischemia promotes 20-HETE increases that drive angiogenesis are unknown. This study aims to address the hypothesis that inflammatory neutrophil-derived myeloperoxidase (MPO) and hypochlorous acid (HOCl) critically contribute to 20-HETE increases leading to ischemic angiogenesis. Using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry, Laser Doppler Perfusion Imaging, and Microvascular Density analysis, we found that neutrophil depletion and MPO knockout mitigate angiogenesis and 20-HETE production in the gracilis muscles of mice subjected to hindlimb ischemia. Furthermore, we found MPO and HOCl to be elevated in these tissues postischemia as assessed by immunofluorescence microscopy and in vivo live imaging of HOCl. Next, we demonstrated that the additions of either HOCl or an enzymatic system for generating HOCl to endothelial cells increase the expression of CYP4A11 and its product, 20-HETE. Finally, pharmacological interference of hypoxia inducible factor (HIF) signaling results in ablation of HOCl-induced CYP4A11 transcript and significant reductions in CYP4A11 protein. Collectively, we conclude that neutrophil-derived MPO and its product HOCl activate HIF-1α and CYP4A11 leading to increased 20-HETE production that drives postischemic compensatory angiogenesis. SIGNIFICANCE STATEMENT: Traditionally, neutrophil derived MPO and HOCl are exclusively associated in the innate immunity as potent bactericidal/virucidal factors. The present study establishes a novel paradigm by proposing a unique function for MPO/HOCl as signaling agents that drive critical physiological angiogenesis by activating the CYP4A11-20-HETE signaling axis via a HIF-1α-dependent mechanism. The findings from this study potentially identify novel therapeutic targets for the treatment of ischemia and other diseases associated with abnormal angiogenesis.
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Affiliation(s)
- Juan A Azcona
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Samantha Tang
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Elizabeth Berry
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Frank F Zhang
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Radha Garvey
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - John R Falck
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Michal Laniado Schwartzman
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Tao Yi
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Thomas M Jeitner
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
| | - Austin M Guo
- Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
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Mu R, Campos de Souza S, Liao Z, Dong L, Wang C. Reprograming the immune niche for skin tissue regeneration - From cellular mechanisms to biomaterials applications. Adv Drug Deliv Rev 2022; 185:114298. [PMID: 35439569 DOI: 10.1016/j.addr.2022.114298] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 02/07/2023]
Abstract
Despite the rapid development of therapeutic approaches for skin repair, chronic wounds such as diabetic foot ulcers remain an unaddressed problem that affects millions of people worldwide. Increasing evidence has revealed the crucial and diverse roles of the immune cells in the development and repair of the skin tissue, prompting new research to focus on further understanding and modulating the local immune niche for comprehensive, 'perfect' regeneration. In this review, we first introduce how different immunocytes and certain stromal cells involved in innate and adaptive immunity coordinate to maintain the immune niche and tissue homeostasis, with emphasis on their specific roles in normal and pathological wound healing. We then discuss novel engineering approaches - particularly biomaterials systems and cellular therapies - to target different players of the immune niche, with three major aims to i) overcome 'under-healing', ii) avoid 'over-healing', and iii) promote functional restoration, including appendage development. Finally, we highlight how these strategies strive to manage chronic wounds and achieve full structural and functional skin recovery by creating desirable 'soil' through modulating the immune microenvironment.
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Depletion of γδ T Cells Leads to Reduced Angiogenesis and Increased Infiltration of Inflammatory M1-like Macrophages in Ischemic Muscle Tissue. Cells 2022; 11:cells11091490. [PMID: 35563796 PMCID: PMC9102774 DOI: 10.3390/cells11091490] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 02/06/2023] Open
Abstract
γδ T cells, a small subset of T cells in blood, play a substantial role in influencing immunoregulatory and inflammatory processes. The functional impact of γδ T cells on angiogenesis in ischemic muscle tissue has never been reported and is the topic of the present work. Femoral artery ligation (FAL) was used to induce angiogenesis in the lower leg of γδ T cell depleted mice and wildtype and isotype antibody-treated control groups. Gastrocnemius muscle tissue was harvested 3 and 7 days after FAL and assessed using (immuno-)histological analyses. Hematoxylin and Eosin staining showed an increased area of tissue damage in γδ T cell depleted mice 7 days after FAL. Impaired angiogenesis was demonstrated by lower capillary to muscle fiber ratio and decreased number of proliferating endothelial cells (CD31+/BrdU+). γδ T cell depleted mice showed an increased number of total leukocytes (CD45+), neutrophils (MPO+) and neutrophil extracellular traps (NETs) (MPO+/CitH3+), without changes in the neutrophils to NETs ratio. Moreover, the depletion resulted in a higher macrophage count (DAPI/CD68+) caused by an increase in inflammatory M1-like macrophages (CD68+/MRC1−). Altogether, we show that depletion of γδ T cells leads to increased accumulation of leukocytes and M1-like macrophages, along with impaired angiogenesis.
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Combined systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) predicts chemotherapy response and prognosis in locally advanced gastric cancer patients receiving neoadjuvant chemotherapy with PD-1 antibody sintilimab and XELOX: a prospective study. BMC Gastroenterol 2022; 22:121. [PMID: 35287591 PMCID: PMC8919583 DOI: 10.1186/s12876-022-02199-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 03/03/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Previous studies have confirmed that systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) can predict the prognosis and chemotherapy efficacy of various malignant tumors. However, to the best of our knowledge, no study investigated the SII combined with PNI score to predict the efficacy of anti-programmed death 1 (anti-PD-1) antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in the treatment of locally advanced gastric cancer. This study aims to evaluate the predictive value of pre-treatment SII-PNI score on the sensitivity of sintilimab immunotherapy combined with XELOX chemotherapy in patients with locally advanced gastric cancer. METHODS We registered a prospective clinical study involving 30 locally advanced gastric cancer patients from March 2020 to July 2021. The pre-treatment SII and PNI were calculated from peripheral blood samples, and the cut-off value was calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 568.5) and low PNI (≤ 52.7); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI. RESULTS All patients were evaluated by RECIST1.1 criteria after four cycles of sintilimab immunotherapy combined with XELOX chemotherapy, including 5 patients with TRG 3 and 25 patients with non-TRG 3. The SII-PNI score of non-TRG 3 patients was significantly lower than that of TRG 3 patients (P = 0.017). The medial progression free survival of patients with low SII-PNI score was significantly better than that of patients with high SII-PNI score (P < 0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting progression-free survival (P = 0.003). CONCLUSION The pre-treatment SII-PNI score is a significant indicator for predicting chemosensitivity of locally advanced patients after sintilimab immunotherapy combined with XELOX chemotherapy, which can help to identify high-risk groups and predict prognosis. TRIAL REGISTRATION The registered name of the trial is "Prospective clinical study of sintilimab combined with chemotherapy for neoadjuvant therapy in locally advanced gastric cancer". Its Current Controlled Trials number is ChiCTR2000030414. Its date of registration is 01/03/2020.
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Ozel I, Duerig I, Domnich M, Lang S, Pylaeva E, Jablonska J. The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer. Cancers (Basel) 2022; 14:cancers14030536. [PMID: 35158807 PMCID: PMC8833332 DOI: 10.3390/cancers14030536] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels from already existing vasculature, is tightly regulated by pro- and anti-angiogenic stimuli and occurs under both physiological and pathological conditions. Tumor angiogenesis is central for tumor development, and an “angiogenic switch” could be initiated by multiple immune cells, such as neutrophils. Tumor-associated neutrophils promote tumor angiogenesis by the release of both conventional and non-conventional pro-angiogenic factors. Therefore, neutrophil-mediated tumor angiogenesis should be taken into consideration in the design of novel anti-cancer therapy. This review recapitulates the complex role of neutrophils in tumor angiogenesis and summarizes neutrophil-derived pro-angiogenic factors and mechanisms regulating angiogenic activity of tumor-associated neutrophils. Moreover, it provides up-to-date information about neutrophil-targeting therapy, complementary to anti-angiogenic treatment.
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Wang JH, Tseng CL, Lin FL, Chen J, Hsieh EH, Lama S, Chuang YF, Kumar S, Zhu L, McGuinness MB, Hernandez J, Tu L, Wang PY, Liu GS. Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization. Theranostics 2022; 12:657-674. [PMID: 34976206 PMCID: PMC8692906 DOI: 10.7150/thno.65098] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 11/07/2021] [Indexed: 11/22/2022] Open
Abstract
Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV. Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results: We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion: Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.
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Affiliation(s)
- Jiang-Hui Wang
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
| | - Ching-Li Tseng
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
| | - Fan-Li Lin
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jinying Chen
- Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Erh-Hsuan Hsieh
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
| | - Suraj Lama
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Yu-Fan Chuang
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Satheesh Kumar
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Linxin Zhu
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Myra B. McGuinness
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
| | - Jessika Hernandez
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Leilei Tu
- Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Peng-Yuan Wang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Guei-Sheung Liu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, Australia
- Aier Eye Institute, Changsha, Hunan, China
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