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Pilard M, Babran S, Martel C. Regulation of Platelet Function by HDL. Arterioscler Thromb Vasc Biol 2025; 45:e184-e200. [PMID: 40207365 DOI: 10.1161/atvbaha.124.318260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Over the past decade, increasing the capacity of HDL (high-density lipoprotein) cholesterol to mediate macrophage reverse cholesterol transport has been a target of interest in the treatment of cardiovascular diseases (CVDs). However, clinical studies reporting the limited efficacy of HDL or its main apolipoprotein, APOA1, in reducing cardiovascular events have emerged. Although HDL cholesterol is unlikely to play a direct causal role in CVD, its inverse, albeit modest, association with CVD risk, consistently observed in large population studies, suggests it may influence alternative pathways beyond cholesterol metabolism. Given the diverse functions of HDL and its components, it is conceivable that its impact on CVD occurs through less direct mechanisms. A potential hypothesis is that HDL modulates platelet function, a crucial player in the initiation and progression of atherothrombosis, which may contribute to its observed relationship with CVD risk. In this review, we focus on how HDL and its components, with an emphasis on APOA1, interact with platelets (and their precursors or activation products) to modulate atherothrombotic responses.
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Affiliation(s)
- Marion Pilard
- Department of Medicine, Faculty of Medicine, Université de Montréal, Canada
- Montreal Heart Institute, Canada
| | - Sara Babran
- Department of Medicine, Faculty of Medicine, Université de Montréal, Canada
- Montreal Heart Institute, Canada
| | - Catherine Martel
- Department of Medicine, Faculty of Medicine, Université de Montréal, Canada
- Montreal Heart Institute, Canada
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2
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Nara R, Notoh H, Sasaki T, Tsukiji N, Shirai T, Kamata A, Suzuki N, Suzuki A, Okamoto S, Kanematsu T, Suzuki N, Katsumi A, Kojima T, Suzuki-Inoue K, Matsushita T, Tamura S. PDPN/CLEC-2 axis modulates megakaryocyte subtypes in a hematopoietic stem cell-regulating megakaryocyte-dominant manner. Thromb Res 2025; 245:109230. [PMID: 39615442 DOI: 10.1016/j.thromres.2024.109230] [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: 02/01/2024] [Revised: 10/30/2024] [Accepted: 11/21/2024] [Indexed: 12/30/2024]
Abstract
INTRODUCTION Megakaryocytes are classified into several subtypes including LSP1-positive immune-skewed, MYLK4-positive hematopoietic stem cell (HSC)-regulating, and BMAL1-positive platelet-producing megakaryocytes. Podoplanin (PDPN)-expressing stromal cells generate a microenvironment that promotes megakaryopoiesis in the bone marrow. In this context, PDPN interacts with C-type lectin-like receptor-2 (CLEC-2) on megakaryocyte progenitors, which induces megakaryocyte proliferation. However, the megakaryocyte subtypes developed by the regulation of the PDPN/CLEC-2 axis have not yet been elucidated. MATERIALS AND METHODS We established an immortalized bone marrow PDPN-expressing stromal cell line and a PDPN-knockout line (PDPN WT and KO feeder cells, respectively). Bone marrow hematopoietic progenitors were committed to megakaryocytes in co-culture with PDPN WT or KO feeder cells. The number and ploidy of megakaryocytes, resultant platelets, and the polarization of megakaryocyte subtypes were investigated. RESULTS The number of megakaryocytes was significantly increased in the co-culture with PDPN WT feeder cells compared to that with PDPN KO feeder cells. The megakaryocytes on the PDPN WT and KO feeders showed their main ploidy at 16 N∼32 N and 8 N∼16 N, respectively. The number of platelets was decreased in the co-culture with the PDPN WT feeder compared to that in the co-culture with the PDPN KO feeder. For each megakaryocyte subtype, the percentage of MYLK4-positive megakaryocytes significantly increased and the percentage of BMAL1-positive megakaryocytes significantly decreased when co-cultured with the PDPN WT feeder. These results were also confirmed in the co-culture of CLEC-2 conditional KO megakaryocytes with PDPN WT feeder cells. CONCLUSION The PDPN/CLEC-2 axis modulates megakaryocyte subtype differentiation, with a predominance of HSC-regulating megakaryocytes.
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Affiliation(s)
- Rikuto Nara
- Graduate School of Health Sciences, Hokkaido University, Japan
| | - Hinako Notoh
- Graduate School of Health Sciences, Hokkaido University, Japan
| | - Tomoyuki Sasaki
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Toshiaki Shirai
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Ayuka Kamata
- Graduate School of Health Sciences, Hokkaido University, Japan
| | - Nobuaki Suzuki
- Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Atsuo Suzuki
- Department of Medical Technique, Nagoya University Hospital, Japan
| | - Shuichi Okamoto
- Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Kanematsu
- Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan
| | - Naruko Suzuki
- Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan
| | - Akira Katsumi
- Department of Hematology, National Center for Geriatrics and Gerontology, Obu City, Japan
| | - Tetsuhito Kojima
- Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan; Aichi Health Promotion Foundation, Nagoya, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Tadashi Matsushita
- Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan; Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan
| | - Shogo Tamura
- Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan; Department of Clinical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
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Yang C, Qu J, Wu J, Cai S, Liu W, Deng Y, Meng Y, Zheng L, Zhang L, Wang L, Guo X. Single-cell dissection reveals immunosuppressive F13A1+ macrophage as a hallmark for multiple primary lung cancers. Clin Transl Med 2024; 14:e70091. [PMID: 39601163 PMCID: PMC11600049 DOI: 10.1002/ctm2.70091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/22/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The increasing prevalence of multiple primarylung cancers (MPLCs) presents challenges to current diagnostic and clinicalmanagement approaches. However, the molecular mechanisms driving MPLCdevelopment and distinguishing it from solitary primary lung cancers (SPLCs)remain largely unexplored. METHODS We performed a comparative single-cell RNAsequencing (scRNA-seq) analysis on tumour and adjacent para-tumour tissues fromMPLC and SPLC patients to comparatively evaluate their immunological landscapes.Additionally, multiplex immunofluorescence (mIF) staining and independentvalidation datasets were used to confirm findings. RESULTS MPLCs and SPLCs share significant similarities in genetic, transcriptomic and immune profiles, suggesting common therapeutic strategies such as EGFR-TKIs andICIs. Notably, an immunosuppressive macrophage subtype, F13A1+ Macrophage (Mϕ), is specifically enriched in MPLCs. This subtype overexpresses M2 macrophagemarkers and exhibits up-regulation of SPP1-CD44/CCL13-ACKR1 interactions, indicatingits role in shaping the immunosuppressive tumour microenvironment and promotingtumour growth in MPLCs. CONCLUSIONS This study unveils shared molecular mechanismsbetween MPLCs and SPLCs, while identifying MPLC-specific cellular and molecularfeatures, such as the role of F13A1+ macrophages. The findings provide novelinsights into MPLC pathogenesis, supporting the development of targetedtherapeutic strategies. KEY POINTS Comparative scRNA-seq analysis reveals significant similarities in genetic, transcriptomicand immune profiles between MPLCs and SPLCs. Identification of a unique immunosuppressive F13A1+ macrophage subtype, preferentially enriched in MPLCs, linked to immune evasion and tumourprogression. SPP1-CD44/CCL13-ACKR1 interactions are crucial in MPLC tumour microenvironment, indicating potential targets for therapeutic intervention.
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Affiliation(s)
- Chenglin Yang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Jiahao Qu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
- Southern University of Science and TechnologyShenzhen CityGuangdong ProvinceChina
| | - Jingting Wu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Songhua Cai
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Wenyi Liu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Youjun Deng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Yiran Meng
- Department of R&DHangzhou Repugene Technology Co., Ltd.HangzhouChina
| | - Liuqing Zheng
- Department of R&DHangzhou Repugene Technology Co., Ltd.HangzhouChina
| | - Lishen Zhang
- Department of R&DHangzhou Repugene Technology Co., Ltd.HangzhouChina
| | - Li Wang
- Department of R&DHangzhou Repugene Technology Co., Ltd.HangzhouChina
| | - Xiaotong Guo
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
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Tsai HJ, Cheng KW, Li JC, Ruan TX, Chang TH, Wang JR, Tseng CP. Identification of Podoplanin Aptamers by SELEX for Protein Detection and Inhibition of Platelet Aggregation Stimulated by C-Type Lectin-like Receptor 2. BIOSENSORS 2024; 14:464. [PMID: 39451677 PMCID: PMC11506057 DOI: 10.3390/bios14100464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/15/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024]
Abstract
Tumor cell-induced platelet aggregation (TCIPA) is a mechanism for the protection of tumor cells in the bloodstream and the promotion of tumor progression and metastases. The platelet C-type lectin-like receptor 2 (CLEC-2) can bind podoplanin (PDPN) on a cancer cell surface to facilitate TCIPA. Selective blockage of PDPN-mediated platelet-tumor cell interaction is a plausible strategy for inhibiting metastases. In this study, we aimed to screen for aptamers, which are the single-stranded DNA oligonucleotides that form a specific three-dimensional structure, bind to specific molecular targets with high affinity and specificity, bind to PDPN, and interfere with PDPN/CLEC-2 interactions. The systematic evolution of ligands by exponential enrichment (SELEX) was employed to enrich aptamers that recognize PDPN. The initial characterization of ssDNA pools enriched by SELEX revealed a PDPN aptamer designated as A1 displaying parallel-type G-quadruplexes and long stem-and-loop structures and binding PDPN with a material with a dissociation constant (Kd) of 1.3 ± 1.2 nM. The A1 aptamer recognized both the native and denatured form of PDPN. Notably, the A1 aptamer was able to quantitatively detect PDPN proteins in Western blot analysis. The A1 aptamer could interfere with the interaction between PDPN and CLEC-2 and inhibit PDPN-induced platelet aggregation in a concentration-dependent manner. These findings indicated that the A1 aptamer is a candidate for the development of biosensors in detecting the levels of PDPN expression. The action by A1 aptamer could result in the prevention of tumor cell metastases, and if so, could become an effective pharmacological agent in treating cancer patients.
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Affiliation(s)
- Hui-Ju Tsai
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Kai-Wen Cheng
- Department of Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jou-Chen Li
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Tsai-Xiang Ruan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ting-Hsin Chang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jin-Ru Wang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ching-Ping Tseng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Graduate Institute of Biomedical Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 33302, Taiwan
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Vachon L, Jean G, Milasan A, Babran S, Lacroix E, Guadarrama Bello D, Villeneuve L, Rak J, Nanci A, Mihalache-Avram T, Tardif JC, Finnerty V, Ruiz M, Boilard E, Tessier N, Martel C. Platelet extracellular vesicles preserve lymphatic endothelial cell integrity and enhance lymphatic vessel function. Commun Biol 2024; 7:975. [PMID: 39128945 PMCID: PMC11317532 DOI: 10.1038/s42003-024-06675-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 08/02/2024] [Indexed: 08/13/2024] Open
Abstract
Lymphatic vessels are essential for preventing the accumulation of harmful components within peripheral tissues, including the artery wall. Various endogenous mechanisms maintain adequate lymphatic function throughout life, with platelets being essential for preserving lymphatic vessel integrity. However, since lymph lacks platelets, their impact on the lymphatic system has long been viewed as restricted to areas where lymphatics intersect with blood vessels. Nevertheless, platelets can also exert long range effects through the release of extracellular vesicles (EVs) upon activation. We observed that platelet EVs (PEVs) are present in lymph, a compartment to which they could transfer regulatory effects of platelets. Here, we report that PEVs in lymph exhibit a distinct signature enabling them to interact with lymphatic endothelial cells (LECs). In vitro experiments show that the internalization of PEVs by LECs maintains their functional integrity. Treatment with PEVs improves lymphatic contraction capacity in atherosclerosis-prone mice. We suggest that boosting lymphatic pumping with exogenous PEVs offers a novel therapeutic approach for chronic inflammatory diseases characterized by defective lymphatics.
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Affiliation(s)
- Laurent Vachon
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | - Gabriel Jean
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | - Andreea Milasan
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | - Sara Babran
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | - Elizabeth Lacroix
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | | | | | - Janusz Rak
- McGill University and Research, Institute of the McGill University Health Centre, Montreal, Canada
- Department of Experimental Medicine, McGill University, Montreal, Canada
| | - Antonio Nanci
- Department of Stomatology, Faculty of Dental Medicine, Université de Montréal, Montreal, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
| | | | - Jean-Claude Tardif
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | | | - Matthieu Ruiz
- Department of Nutrition, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Metabolomics platform, Montreal, Canada
| | - Eric Boilard
- Centre de Recherche ARThrite - Arthrite, Recherche, Traitements, Université Laval, Québec, Québec, Canada
- Infectious and Immune Diseases Axis, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, Québec, Canada
| | - Nolwenn Tessier
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada
- Montreal Heart Institute, Montreal, Canada
| | - Catherine Martel
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada.
- Montreal Heart Institute, Montreal, Canada.
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Smood B, Smith C, Dori Y, Mavroudis CD, Fuller S, Gaynor JW, Maeda K. Lymphatic failure and lymphatic interventions: Knowledge gaps and future directions for a new frontier in congenital heart disease. Semin Pediatr Surg 2024; 33:151426. [PMID: 38820801 PMCID: PMC11229519 DOI: 10.1016/j.sempedsurg.2024.151426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
Lymphatic failure is a broad term that describes the lymphatic circulation's inability to adequately transport fluid and solutes out of the interstitium and into the systemic venous circulation, which can result in dysfunction and dysregulation of immune responses, dietary fat absorption, and fluid balance maintenance. Several investigations have recently elucidated the nexus between lymphatic failure and congenital heart disease, and the associated morbidity and mortality is now well-recognized. However, the precise pathophysiology and pathogenesis of lymphatic failure remains poorly understood and relatively understudied, and there are no targeted therapeutics or interventions to reliably prevent its development and progression. Thus, there is growing enthusiasm towards the development and application of novel percutaneous and surgical lymphatic interventions. Moreover, there is consensus that further investigations are needed to delineate the underlying mechanisms of lymphatic failure, which could help identify novel therapeutic targets and develop innovative procedures to improve the overall quality of life and survival of these patients. With these considerations, this review aims to provide an overview of the lymphatic circulation and its vasculature as it relates to current understandings into the pathophysiology and pathogenesis of lymphatic failure in patients with congenital heart disease, while also summarizing strategies for evaluating and managing lymphatic complications, as well as specific areas of interest for future translational and clinical research efforts.
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Affiliation(s)
- Benjamin Smood
- Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States of America; Division of Cardiovascular Surgery, Department of Surgery, The University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
| | - Christopher Smith
- Jill and Mark Fishman Center for Lymphatic Disorders, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104 United States of America
| | - Yoav Dori
- Jill and Mark Fishman Center for Lymphatic Disorders, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104 United States of America
| | - Constantine D Mavroudis
- Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States of America; Division of Cardiovascular Surgery, Department of Surgery, The University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America
| | - Stephanie Fuller
- Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States of America; Division of Cardiovascular Surgery, Department of Surgery, The University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America
| | - J William Gaynor
- Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States of America; Division of Cardiovascular Surgery, Department of Surgery, The University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America
| | - Katsuhide Maeda
- Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States of America; Division of Cardiovascular Surgery, Department of Surgery, The University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America; Jill and Mark Fishman Center for Lymphatic Disorders, Children's Hospital of Philadelphia, Philadelphia, PA, United States
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Tsukiji N, Yokomori R, Takusagawa K, Shirai T, Oishi S, Sasaki T, Takano K, Suzuki-Inoue K. C-type lectin-like receptor-2 in platelets mediates ferric chloride-induced platelet activation and attenuates ferroptosis of endothelial cells. J Thromb Haemost 2024; 22:1749-1757. [PMID: 38811291 DOI: 10.1016/j.jtha.2024.03.003] [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: 09/04/2023] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND An iron overload status induces ferroptosis, an iron-dependent nonapoptotic cell death, in various pathological conditions. We previously reported that hemin (heme), protoporphyrin-IX with ferric iron, activates platelets via C-type lectin-like receptor-2 (CLEC-2) and glycoprotein VI/FcRγ, but protoporphyrin-IX alone blocks CLEC-2-dependent platelet activation. Therefore, we hypothesized that free iron has the ability to activate platelets. OBJECTIVES This study aimed to elucidate platelet activation mechanisms of iron (ferric chloride), including the identification of signaling pathways and receptors, and to examine whether platelets regulate ferroptosis. METHODS Platelet aggregometry, platelet activation marker expression, and protein phosphorylation were examined in ferric chloride-stimulated human and murine platelets. Inhibitors of platelet activation signaling pathways and receptor-deleted platelets were utilized to identify the responsible signaling pathway and receptor. The effect of platelets on ferroptosis of endothelial cells was investigated in vitro. RESULTS Ferric chloride induced platelet activation dependent on Src family kinase pathways in humans and mice. Ferric chloride-induced platelet aggregation was almost lost in CLEC-2-depleted murine platelets and wild-type platelets preincubated with recombinant CLEC-2 proteins. Furthermore, coculture of wild-type platelets, but not CLEC-2-deficient platelets, attenuated ferroptosis of endothelial cells in vitro. CONCLUSION Ferric chloride activates platelets via CLEC-2 and Src family kinase pathways, and platelets have a protective role in the ferroptosis of endothelial cells dependent on CLEC-2.
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Affiliation(s)
- Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Ryohei Yokomori
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | | | - Toshiaki Shirai
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Saori Oishi
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Tomoyuki Sasaki
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Katsuhiro Takano
- Department of Transfusion and Cell Therapy, University of Yamanashi Hospital, Chuo, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan; Department of Transfusion and Cell Therapy, University of Yamanashi Hospital, Chuo, Japan.
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8
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Yamazaki E, Ikeda K, Urata R, Ueno D, Katayama A, Ito F, Ikegaya H, Matoba S. Endothelial CLEC-1b plays a protective role against cancer hematogenous metastasis. Biochem Biophys Res Commun 2024; 708:149819. [PMID: 38531221 DOI: 10.1016/j.bbrc.2024.149819] [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: 03/04/2024] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
Metastasis, which is the spread of cancer cells into distant organs, is a critical determinant of prognosis in patients with cancer, and blood vessels are the major route for cancer cells to spread systemically. Extravasation is a critical process for the hematogenous metastasis; however, its underlying molecular mechanisms remain poorly understood. Here, we identified that senescent ECs highly express C-type lectin domain family 1 member B (CLEC-1b), and that endothelial CLEC-1b inhibits the hematogenous metastasis of a certain type of cancer. CLEC-1b expression was enhanced in ECs isolated from aged mice, senescent cultured human ECs, and ECs of aged human. CLEC-1b overexpression in ECs prevented the disruption of endothelial integrity, and inhibited the transendothelial migration of cancer cells expressing podoplanin (PDPN), a ligand for CLEC-1b. Notably, target activation of CLEC-1b in ECs decreased the hematogenous metastasis in the lungs by cancer cells expressing PDPN in mice. Our data reveal the protective role of endothelial CLEC-1b against cancer hematogenous metastasis. Considering the high CLEC-1b expression in senescent ECs, EC senescence may play a beneficial role with respect to the cancer hematogenous metastasis.
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Affiliation(s)
- Ekura Yamazaki
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Koji Ikeda
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan; Department of Epidemiology for Longevity and Regional Health, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan.
| | - Ryota Urata
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Daisuke Ueno
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Akiko Katayama
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Fumiaki Ito
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Hiroshi Ikegaya
- Department of Forensics Medicine, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Satoaki Matoba
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
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9
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Suzuki-Inoue K, Tsukiji N. A role of platelet C-type lectin-like receptor-2 and its ligand podoplanin in vascular biology. Curr Opin Hematol 2024; 31:130-139. [PMID: 38359177 DOI: 10.1097/moh.0000000000000805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
PURPOSE OF REVIEW Platelets are essential for hemostasis and are also vital in lymphatic and lung development and the maintenance of vascular integrity. Platelet activation receptor C-type lectin-like receptor 2 (CLEC-2) and its endogenous ligand podoplanin (PDPN) in lymphatic endothelial cells (LECs) and other cells regulate these processes. This review aims to comprehensively summarize the roles of platelet CLEC-2 and PDPN. This review also focuses on discussing the underlying mechanisms by which platelet CLEC-2 and PDPN mediate blood/lymphatic separation. FINDINGS CLEC-2/PDPN-induced platelet activation in the primary lymph sacs, developmental lymphovenous junctions, neonatal mesentery, and the site of tumor lymphangiogenesis prevents blood/lymphatic vessel misconnection. Further, CLEC-2/PDPN-induced platelet activation is essential for lung development. Mice deficient in CLEC-2 or PDPN show blood-filled lymphatics, lung malformations, and cerebrovascular abnormalities. CLEC-2 deletion in steady-state adult mice did not result in blood/lymphatic vessel mixing. In adulthood, CLEC-2 maintains vascular integrity and that of high endothelial venules in lymph nodes. CLEC-2 deletion in adulthood results in hemorrhage under inflammatory conditions, and hemolymph nodes. SUMMARY The platelet CLEC-2/LEC PDPN interaction prevents blood/lymphatic vessel mixing at active remodeling sites of the blood/lymphatic system, but not in steady-state adult mice. This interaction also regulates vascular integrity when vascular permeability increases before and after birth.
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Affiliation(s)
- Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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10
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Costanzo A, Clarke D, Holt M, Sharma S, Nagy K, Tan X, Kain L, Abe B, Luce S, Boitard C, Wyseure T, Mosnier LO, Su AI, Grimes C, Finn MG, Savage PB, Gottschalk M, Pettus J, Teyton L. Repositioning the Early Pathology of Type 1 Diabetes to the Extraislet Vasculature. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1094-1104. [PMID: 38426888 PMCID: PMC10944819 DOI: 10.4049/jimmunol.2300769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024]
Abstract
Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.
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Affiliation(s)
- Anne Costanzo
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Don Clarke
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Marie Holt
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Siddhartha Sharma
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Kenna Nagy
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Xuqian Tan
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
| | - Lisa Kain
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Brian Abe
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | | | | | - Tine Wyseure
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
| | - Laurent O. Mosnier
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
| | - Andrew I. Su
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
| | - Catherine Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE
| | - M. G. Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA
| | - Paul B. Savage
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT
| | - Michael Gottschalk
- Rady Children’s Hospital, University of California San Diego, San Diego, CA
| | - Jeremy Pettus
- UC San Diego School of Medicine, University of California San Diego, San Diego, CA
| | - Luc Teyton
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
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11
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Sun L, Wang Z, Liu Z, Mu G, Cui Y, Xiang Q. C-type lectin-like receptor 2: roles and drug target. Thromb J 2024; 22:27. [PMID: 38504248 PMCID: PMC10949654 DOI: 10.1186/s12959-024-00594-8] [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: 01/06/2024] [Accepted: 03/07/2024] [Indexed: 03/21/2024] Open
Abstract
C-type lectin-like receptor-2 (CLEC-2) is a member of the C-type lectin superfamily of cell surface receptors. The first confirmed endogenous and exogenous ligands of CLEC-2 are podoplanin and rhodocytin, respectively. CLEC-2 is expressed on the surface of platelets, which participates in platelet activation and aggregation by binding with its ligands. CLEC-2 and its ligands are involved in pathophysiological processes, such as atherosclerosis, cancer, inflammatory thrombus status, maintenance of vascular wall integrity, and cancer-related thrombosis. In the last 5 years, different anti- podoplanin antibody types have been developed for the treatment of cancers, such as glioblastoma and lung cancer. New tests and new diagnostics targeting CLEC-2 are also discussed. CLEC-2 mediates thrombosis in various pathological states, but CLEC-2-specific deletion does not affect normal hemostasis, which would provide a new therapeutic tool for many thromboembolic diseases. The CLEC-2-podoplanin interaction is a target for cancer treatment. CLEC-2 may be applied in clinical practice and play a therapeutic role.
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Affiliation(s)
- Lan Sun
- Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing, 100034, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhe Wang
- Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing, 100034, China
- Institute of Clinical Pharmacology, Peking University, Beijing, China
| | - Zhiyan Liu
- Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing, 100034, China
- Institute of Clinical Pharmacology, Peking University, Beijing, China
| | - Guangyan Mu
- Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing, 100034, China
- Institute of Clinical Pharmacology, Peking University, Beijing, China
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing, 100034, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
- Institute of Clinical Pharmacology, Peking University, Beijing, China
| | - Qian Xiang
- Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing, 100034, China.
- Institute of Clinical Pharmacology, Peking University, Beijing, China.
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12
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Zhou YW, Ren Y, Lu MM, Xu LL, Cheng WX, Zhang MM, Ding LP, Chen D, Gao JG, Du J, Jin CL, Chen CX, Li YF, Cheng T, Jiang PL, Yang YD, Qian PX, Xu PF, Jin X. Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data. World J Gastroenterol 2024; 30:34-49. [PMID: 38293325 PMCID: PMC10823898 DOI: 10.3748/wjg.v30.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/08/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024] Open
Abstract
Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.
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Affiliation(s)
- Yu-Wei Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yue Ren
- Department of Gastroenterology, The Second Hospital of Jiaxing, Jiaxing 314000, Zhejiang Province, China
| | - Miao-Miao Lu
- Endoscopy Center, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ling-Ling Xu
- Department of Gastroenterology, The Second People’s Hospital of Yuhang District, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Xin Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Meng Zhang
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou 310003, Zhejiang Province, China
| | - Lin-Ping Ding
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Dong Chen
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Guo Gao
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Juan Du
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ci-Liang Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Chun-Xiao Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yun-Fei Li
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Tao Cheng
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Peng-Lei Jiang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Da Yang
- Department of Infectious Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Peng-Xu Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Peng-Fei Xu
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xi Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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13
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Oishi S, Tsukiji N, Segawa T, Takano K, Hasuda N, Suzuki-Inoue K. Abnormalities in C-type lectin-like receptor 2 in a patient with Gorham-Stout disease: the first case report. Res Pract Thromb Haemost 2024; 8:102273. [PMID: 38187828 PMCID: PMC10770757 DOI: 10.1016/j.rpth.2023.102273] [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: 06/09/2023] [Revised: 10/10/2023] [Accepted: 11/12/2023] [Indexed: 01/09/2024] Open
Abstract
Background Gorham-Stout disease (GSD) is a form of lymphangiomatosis of unknown etiology, characterized by abnormal distribution of lymphatic vessels. Platelets and lymphangiogenesis are closely related via C-type lectin-like receptor 2 (CLEC-2)/podoplanin. Key Clinical Question Despite similarities between abnormal lymphatic vessels in CLEC-2-deficient mice and patients with GSD, whether CLEC-2 on platelets is involved in GSD pathogenesis is unknown. Clinical Approach We examined CLEC-2 expression in platelets of a patient with lethal GSD. Most of the patient's platelets expressed aberrant CLEC-2 that was not detectable by certain monoclonal antibodies for human CLEC-2. Further, this population was not activated by a CLEC-2-activating snake venom, rhodocytin. Possible causes of abnormal CLEC-2 including anti-CLEC-2 autoantibodies, podoplanin binding to CLEC-2, and pathogenic CLEC1B gene alteration were excluded. Conclusions We believe that this is the first report of a patient with structurally and functionally abnormal CLEC-2. CLEC-2 abnormality may be associated with dysregulated lymphangiogenesis in GSD.
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Affiliation(s)
- Saori Oishi
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Takahiro Segawa
- Center for Life Science Research, University of Yamanashi, Japan
| | - Katsuhiro Takano
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Norio Hasuda
- Department of Surgery, University of Yamanashi, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
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14
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Fan F, Su B, Kolodychak A, Ekwueme E, Alderfer L, Saha S, Webber MJ, Hanjaya-Putra D. Hyaluronic Acid Hydrogels with Phototunable Supramolecular Cross-Linking for Spatially Controlled Lymphatic Tube Formation. ACS APPLIED MATERIALS & INTERFACES 2023; 15:58181-58195. [PMID: 38065571 PMCID: PMC10739586 DOI: 10.1021/acsami.3c12514] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/22/2023]
Abstract
The dynamics of the extracellular matrix (ECM) influences stem cell differentiation and morphogenesis into complex lymphatic networks. While dynamic hydrogels with stress relaxation properties have been developed, many require detailed chemical processing to tune viscoelasticity, offering a limited opportunity for in situ and spatiotemporal control. Here, a hyaluronic acid (HA) hydrogel is reported with viscoelasticity that is controlled and spatially tunable using UV light to direct the extent of supramolecular and covalent cross-linking interactions. This is achieved using UV-mediated photodimerization of a supramolecular ternary complex of pendant trans-Brooker's Merocyanine (BM) guests and a cucurbit[8]uril (CB[8]) macrocycle. The UV-mediated conversion of this supramolecular complex to its covalent photodimerized form is catalyzed by CB[8], offering a user-directed route to spatially control hydrogel dynamics in combination with orthogonal photopatterning by UV irradiation through photomasks. This material thus achieves spatial heterogeneity of substrate dynamics, recreating features of native ECM without the need for additional chemical reagents. Moreover, these dynamic hydrogels afford spatial control of substrate mechanics to direct human lymphatic endothelial cells (LECs) to form lymphatic cord-like structures (CLS). Specifically, cells cultured on viscoelastic supramolecular hydrogels have enhanced formation of CLS, arising from increased expression of key lymphatic markers, such as LYVE-1, Podoplanin, and Prox1, compared to static elastic hydrogels prepared from fully covalent cross-linking. Viscoelastic hydrogels promote lymphatic CLS formation through the expression of Nrp2, VEGFR2, and VEGFR3 to enhance the VEGF-C stimulation. Overall, viscoelastic supramolecular hydrogels offer a facile route to spatially control lymphatic CLS formation, providing a tool for future studies of basic lymphatic biology and tissue engineering applications.
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Affiliation(s)
- Fei Fan
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Bo Su
- Chemical
and Biomolecular Engineering, University
of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Alexander Kolodychak
- Chemical
and Biomolecular Engineering, University
of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Ephraim Ekwueme
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Laura Alderfer
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Sanjoy Saha
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Matthew J. Webber
- Chemical
and Biomolecular Engineering, University
of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Donny Hanjaya-Putra
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
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15
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Yokomori R, Shirai T, Tsukiji N, Oishi S, Sasaki T, Takano K, Suzuki-Inoue K. C-type lectin-like receptor-2 (CLEC-2) is a key regulator of kappa-carrageenan-induced tail thrombosis model in mice. Platelets 2023; 34:2281941. [PMID: 38010137 DOI: 10.1080/09537104.2023.2281941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/03/2023] [Indexed: 11/29/2023]
Abstract
Kappa-carrageenan (KCG), which is used to induce thrombosis in laboratory animals for antithrombotic drug screening, can trigger platelet aggregation. However, the cell-surface receptor and related signaling pathways remain unclear. In this study, we investigated the molecular basis of KCG-induced platelet activation using light-transmittance aggregometry, flow cytometry, western blotting, and surface plasmon resonance assays using platelets from platelet receptor-deficient mice and recombinant proteins. KCG-induced tail thrombosis was also evaluated in mice lacking the platelet receptor. We found that KCG induces platelet aggregation with α-granule secretion, activated integrin αIIbβ3, and phosphatidylserine exposure. As this aggregation was significantly inhibited by the Src family kinase inhibitor and spleen tyrosine kinase (Syk) inhibitor, a tyrosine kinase-dependent pathway is required. Platelets exposed to KCG exhibited intracellular tyrosine phosphorylation of Syk, linker activated T cells, and phospholipase C gamma 2. KCG-induced platelet aggregation was abolished in platelets from C-type lectin-like receptor-2 (CLEC-2)-deficient mice, but not in platelets pre-treated with glycoprotein VI-blocking antibody, JAQ1. Surface plasmon resonance assays showed a direct association between murine/human recombinant CLEC-2 and KCG. KCG-induced thrombosis and thrombocytopenia were significantly inhibited in CLEC-2-deficient mice. Our findings show that KCG induces platelet activation via CLEC-2.
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Affiliation(s)
- Ryohei Yokomori
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Kofu, Japan
| | - Toshiaki Shirai
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Kofu, Japan
| | - Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Kofu, Japan
| | - Saori Oishi
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Kofu, Japan
| | - Tomoyuki Sasaki
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Kofu, Japan
| | - Katsuhiro Takano
- Department of Transfusion and Cell Therapy, University of Yamanashi Hospital, Chuo, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Kofu, Japan
- Department of Transfusion and Cell Therapy, University of Yamanashi Hospital, Chuo, Japan
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16
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Shirai T, Tsukiji N, Sasaki T, Oishi S, Yokomori R, Takano K, Suzuki-Inoue K. Cancer-associated fibroblasts promote venous thrombosis through podoplanin/CLEC-2 interaction in podoplanin-negative lung cancer mouse model. J Thromb Haemost 2023; 21:3153-3165. [PMID: 37473844 DOI: 10.1016/j.jtha.2023.07.005] [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: 02/13/2023] [Revised: 06/12/2023] [Accepted: 07/03/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Cancer-associated thrombosis (CAT) is the leading cause of morbidity and mortality. Cancer-associated fibroblasts (CAFs) are a prominent component of the tumor microenvironment that contributes to cancer progression through direct cell-cell interactions and the release of extracellular vesicles (EVs). However, the role of CAFs in CAT remains unclear. OBJECTIVE This study aims to investigate whether CAFs aggravate CAT and the underlying molecular mechanism using a preclinical mouse lung cancer model. METHODS We designed a Lewis lung carcinoma (LLC) tumor-bearing mouse model. CAFs were characterized using fluorescence immunohistostaining. The presence of podoplanin, a platelet-activating membrane protein through C-type lectin-like receptor 2 (CLEC-2), in EVs isolated from primary CAFs or LLC tumor tissues was assessed by immunoblotting. The platelet activation and aggregation abilities of the EVs were quantified using flow cytometry. Podoplanin plasma levels were measured by enzyme-linked immunosorbent assay. Venous thrombosis was induced in the femoral vein using 2.5% ferric chloride. The anti-CLEC-2 monoclonal antibody 2A2B10 was used to deplete CLEC-2 on the surface of the platelets. RESULTS CAFs expressing CD90, PDGFRβ, HSP47, CD34, and vimentin, co-expressed podoplanin and induced platelet activation and aggregation in a CLEC-2-dependent manner. Tumor-bearing mice showed elevated podoplanin plasma levels. CAF-EV injection and tumor-bearing mice showed shorter occlusion time in the venous thrombosis model. Although tumor growth was not altered, antibody-induced CLEC-2 depletion suppressed venous thrombosis in the tumor-bearing state but not in the healthy condition. CONCLUSION CAFs and CAF-derived EVs induce CLEC-2-dependent platelet aggregation and aggravate venous thrombosis.
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Affiliation(s)
- Toshiaki Shirai
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Tomoyuki Sasaki
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Saori Oishi
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Ryohei Yokomori
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Katsuhiro Takano
- Department of Transfusion and Cell Therapy, University of Yamanashi Hospital, Chuo, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan; Department of Transfusion and Cell Therapy, University of Yamanashi Hospital, Chuo, Japan.
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17
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Tsukiji N, Suzuki-Inoue K. Impact of Hemostasis on the Lymphatic System in Development and Disease. Arterioscler Thromb Vasc Biol 2023; 43:1747-1754. [PMID: 37534465 DOI: 10.1161/atvbaha.123.318824] [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: 03/13/2023] [Accepted: 07/20/2023] [Indexed: 08/04/2023]
Abstract
Lymphatic vessels form a systemic network that maintains interstitial fluid homeostasis and regulates immune responses and is strictly separated from the circulatory system. During embryonic development, lymphatic endothelial cells originate from blood vascular endothelial cells in the cardinal veins and form lymph sacs. Platelets are critical for separating lymph sacs from the cardinal veins through interactions between CLEC-2 (C-type lectin-like receptor-2) and PDPN (podoplanin) in lymphatic endothelial cells. Therefore, deficiencies of these genes cause blood-filled lymphatic vessels, leading to abnormal lymphatic vessel maturation. The junction between the thoracic duct and the subclavian vein has valves and forms physiological thrombi dependent on CLEC-2/PDPN signaling to prevent blood backflow into the thoracic duct. In addition, platelets regulate lymphangiogenesis and maintain blood/lymphatic separation in pathological conditions, such as wound healing and inflammatory diseases. More recently, it was reported that the entire hemostatic system is involved in lymphangiogenesis. Thus, the hemostatic system plays a crucial role in the establishment, maintenance, and rearrangement of lymphatic networks and contributes to body fluid homeostasis, which suggests that the hemostatic system is a potential target for treating lymphatic disorders. This review comprehensively summarizes the role of the hemostatic system in lymphangiogenesis and lymphatic vessel function and discusses challenges and future perspectives.
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Affiliation(s)
- Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
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18
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Fuseya S, Izumi H, Hamano A, Murakami Y, Suzuki R, Koiwai R, Hayashi T, Kuno A, Takahashi S, Kudo T. Reduction in disialyl-T antigen levels in mice deficient for both St6galnac3 and St6galnac4 results in blood filling of lymph nodes. Sci Rep 2023; 13:10582. [PMID: 37386100 PMCID: PMC10310836 DOI: 10.1038/s41598-023-37363-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/20/2023] [Indexed: 07/01/2023] Open
Abstract
Sialic acid (SA) is present at the terminal ends of carbohydrate chains in glycoproteins and glycolipids and is involved in various biological phenomena. The biological function of the disialyl-T (SAα2-3Galβ1-3(SAα2-6)GalNAcα1-O-Ser/Thr) structure is largely unknown. To elucidate the role of disialyl-T structure and determine the key enzyme from the N-acetylgalactosaminide α2,6-sialyltransferase (St6galnac) family involved in its in vivo synthesis, we generated St6galnac3- and St6galnac4-deficient mice. Both single-knockout mice developed normally without any prominent phenotypic abnormalities. However, the St6galnac3::St6galnact4 double knockout (DKO) mice showed spontaneous hemorrhage of the lymph nodes (LN). To identify the cause of bleeding in the LN, we examined podoplanin, which modifies the disialyl-T structures. The protein expression of podoplanin in the LN of DKO mice was similar to that in wild-type mice. However, the reactivity of MALII lectin, which recognizes disialyl-T, in podoplanin immunoprecipitated from DKO LN was completely abolished. Moreover, the expression of vascular endothelial cadherin was reduced on the cell surface of high endothelial venule (HEV) in the LN, suggesting that hemorrhage was caused by the structural disruption of HEV. These results suggest that podoplanin possesses disialyl-T structure in mice LN and that both St6galnac3 and St6galnac4 are required for disialyl-T synthesis.
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Affiliation(s)
- Sayaka Fuseya
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, 305-8565, Japan
| | - Hiroyuki Izumi
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Ayane Hamano
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yuka Murakami
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- School of Integrative and Global Majors, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Riku Suzuki
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Rikako Koiwai
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Takuto Hayashi
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Atsushi Kuno
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, 305-8565, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Takashi Kudo
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
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19
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Jeong DP, Montes D, Chang HC, Hanjaya-Putra D. Fractal dimension to characterize interactions between blood and lymphatic endothelial cells. Phys Biol 2023; 20:045004. [PMID: 37224822 PMCID: PMC10258918 DOI: 10.1088/1478-3975/acd898] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/02/2023] [Accepted: 05/24/2023] [Indexed: 05/26/2023]
Abstract
Spatial patterning of different cell types is crucial for tissue engineering and is characterized by the formation of sharp boundary between segregated groups of cells of different lineages. The cell-cell boundary layers, depending on the relative adhesion forces, can result in kinks in the border, similar to fingering patterns between two viscous partially miscible fluids which can be characterized by its fractal dimension. This suggests that mathematical models used to analyze the fingering patterns can be applied to cell migration data as a metric for intercellular adhesion forces. In this study, we develop a novel computational analysis method to characterize the interactions between blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), which form segregated vasculature by recognizing each other through podoplanin. We observed indiscriminate mixing with LEC-LEC and BEC-BEC pairs and a sharp boundary between LEC-BEC pair, and fingering-like patterns with pseudo-LEC-BEC pairs. We found that the box counting method yields fractal dimension between 1 for sharp boundaries and 1.3 for indiscriminate mixing, and intermediate values for fingering-like boundaries. We further verify that these results are due to differential affinity by performing random walk simulations with differential attraction to nearby cells and generate similar migration pattern, confirming that higher differential attraction between different cell types result in lower fractal dimensions. We estimate the characteristic velocity and interfacial tension for our simulated and experimental data to show that the fractal dimension negatively correlates with capillary number (Ca), further indicating that the mathematical models used to study viscous fingering pattern can be used to characterize cell-cell mixing. Taken together, these results indicate that the fractal analysis of segregation boundaries can be used as a simple metric to estimate relative cell-cell adhesion forces between different cell types.
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Affiliation(s)
- Donghyun Paul Jeong
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
| | - Daniel Montes
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
| | - Hsueh-Chia Chang
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Center for Stem Cell and Regenerative Medicine, University of Notre Dame, Notre Dame, IN 46556, United States of America
| | - Donny Hanjaya-Putra
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Center for Stem Cell and Regenerative Medicine, University of Notre Dame, Notre Dame, IN 46556, United States of America
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20
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Bonente D, Bianchi L, De Salvo R, Nicoletti C, De Benedetto E, Bacci T, Bini L, Inzalaco G, Franci L, Chiariello M, Tosi GM, Bertelli E, Barone V. Co-Expression of Podoplanin and CD44 in Proliferative Vitreoretinopathy Epiretinal Membranes. Int J Mol Sci 2023; 24:ijms24119728. [PMID: 37298679 DOI: 10.3390/ijms24119728] [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: 05/07/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs' extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial-mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy.
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Affiliation(s)
- Denise Bonente
- Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Laura Bianchi
- Section of Functional Proteomics, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Rossana De Salvo
- Section of Functional Proteomics, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Claudio Nicoletti
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Elena De Benedetto
- Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Tommaso Bacci
- Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Luca Bini
- Section of Functional Proteomics, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Giovanni Inzalaco
- Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100 Siena, Italy
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Via Fiorentina 1, 53100 Siena, Italy
- Department of Medical Biotechnologies, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Lorenzo Franci
- Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100 Siena, Italy
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Via Fiorentina 1, 53100 Siena, Italy
| | - Mario Chiariello
- Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100 Siena, Italy
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Via Fiorentina 1, 53100 Siena, Italy
| | - Gian Marco Tosi
- Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Eugenio Bertelli
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Virginia Barone
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
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21
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Abstract
The formation of new blood and lymphatic vessels is essential for both the development of multicellular organisms and (patho)physiological processes like wound repair and tumor growth. In the 1990s, circulating blood platelets were first postulated to regulate tumor angiogenesis by interacting with the endothelium and releasing angiogenic regulators from specialized α granules. Since then, many studies have validated the contributions of platelets to tumor angiogenesis, while uncovering novel roles for platelets in other angiogenic processes like wound resolution and retinal vascular disease. Although the majority of (lymph)angiogenesis occurs during development, platelets appear necessary for lymphatic but not vascular growth, implying their particular importance in pathological cases of adult angiogenesis. Future work is required to determine whether drugs targeting platelet production or function offer a clinically relevant tool to limit detrimental angiogenesis.
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Affiliation(s)
- Harvey G Roweth
- Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Elisabeth M Battinelli
- Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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22
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Lampejo AO, Ghavimi SAA, Hägerling R, Agarwal S, Murfee WL. Lymphatic/blood vessel plasticity: motivation for a future research area based on present and past observations. Am J Physiol Heart Circ Physiol 2023; 324:H109-H121. [PMID: 36459445 PMCID: PMC9829479 DOI: 10.1152/ajpheart.00612.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 12/04/2022]
Abstract
The lymphatic system plays a significant role in homeostasis and drainage of excess fluid back into venous circulation. Lymphatics are also associated with a number of diseases including lymphedema, tumor metastasis, and various lymphatic malformations. Emerging evidence suggests that lymphatics might have a bigger connection to the blood vascular system than originally presumed. As these two systems are often studied in isolation, several knowledge gaps exist surrounding what constitutes lymphatic vascular plasticity, under what conditions it arises, and where structures characteristic of plasticity can form. The objective of this review is to overview current structural, cell lineage-based, and cell identity-based evidence for lymphatic plasticity. These examples of plasticity will then be considered in the context of potential clinical and surgical implications of this evolving research area. This review details our current understanding of lymphatic plasticity, highlights key unanswered questions in the field, and motivates future research aimed at clarifying the role and therapeutic potential of lymphatic plasticity in disease.
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Affiliation(s)
- Arinola O Lampejo
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | | | - René Hägerling
- Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
- Clinician Scientist Program, Berlin Institute of Health Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Shailesh Agarwal
- Division of Plastic and Reconstructive Surgery, Brigham and Women's Hospital, Boston, Massachusetts
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
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23
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Tanaka K, Tanaka M, Watanabe N, Ito M, Pastan I, Koizumi M, Matsusaka T. C-type lectin-like receptor (CLEC)-2, the ligand of podoplanin, induces morphological changes in podocytes. Sci Rep 2022; 12:22356. [PMID: 36572741 PMCID: PMC9792514 DOI: 10.1038/s41598-022-26456-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 12/15/2022] [Indexed: 12/28/2022] Open
Abstract
Podoplanin (PDPN) is intensely expressed on the podocyte membrane in an evolutionally conserved manner. CLEC-2, the endogenous ligand of PDPN, is highly expressed in platelets and also exists in a soluble form in plasma. Normally, podocytes are sequestered from CLEC-2, but when the glomerular barrier is injured, podocytes gain access to CLEC-2. We tested the effects of CLEC-2 in podocytes in vitro and in vivo. Cultured podocytes treated with Fc-CLEC-2 demonstrated that CLEC-2 induced the dephosphorylation of ezrin, radixin, and moesin (ERM) proteins. Podocytes treated with Fc-CLEC-2 also showed the dissociation of F-actin filaments from PDPN, F-actin degradation, detachment, and round morphology. Next, we perfused normal mouse kidney in vivo with FLAG-CLEC-2. CLEC-2 induced dephosphorylation of ERM and widening of the foot processes of podocytes. Platelets were detected by immunostaining for CD41 in the urine of mice with podocyte injury, indicating that podocytes can encounter platelets when glomeruli are injured. Collectively, these observations suggest that when platelets leak through the injured glomeruli, CLEC-2 from the platelets acts on PDPN in podocytes and induces morphological change and detachment, which may further aggravate podocyte injury. Thus, PDPN on podocytes may work as a leaked-platelet sensor.
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Affiliation(s)
- Keiko Tanaka
- grid.265061.60000 0001 1516 6626Departments of Basic Medicine, Tokai University School of Medicine, Isehara, Japan ,grid.412342.20000 0004 0631 9477Division of Kidney, Diabetes and Endocrine Diseases, Okayama University Hospital, Okayama, Japan
| | - Masafumi Tanaka
- grid.265061.60000 0001 1516 6626Molecular Life Science, Tokai University School of Medicine, Isehara, Japan
| | - Nobuo Watanabe
- grid.265061.60000 0001 1516 6626Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masatoshi Ito
- grid.265061.60000 0001 1516 6626Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Japan
| | - Ira Pastan
- grid.48336.3a0000 0004 1936 8075Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD USA
| | - Masahiro Koizumi
- grid.265061.60000 0001 1516 6626Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Taiji Matsusaka
- grid.265061.60000 0001 1516 6626Departments of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
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24
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Abstract
The term "lectin" is derived from the Latin word lego- (aggregate) (Boyd & Shapleigh, 1954). Indeed, lectins' folds can flexibly alter their pocket structures just like Lego blocks, which enables them to grab a wide-variety of substances. Thus, this useful fold is well-conserved among various organisms. Through evolution, prototypic soluble lectins acquired transmembrane regions and signaling motifs to become C-type lectin receptors (CLRs). While CLRs seem to possess certain intrinsic affinity to self, some CLRs adapted to efficiently recognize glycoconjugates present in pathogens as pathogen-associated molecular patterns (PAMPs) and altered self. CLRs further extended their diversity to recognize non-glycosylated targets including pathogens and self-derived molecules. Thus, CLRs seem to have developed to monitor the internal/external stresses to maintain homeostasis by sensing various "unfamiliar" targets. In this review, we will summarize recent advances in our understanding of CLRs, their ligands and functions and discuss future perspectives.
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Affiliation(s)
- Carla Guenther
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Masamichi Nagae
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Sho Yamasaki
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
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25
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Jeong DP, Hall E, Neu E, Hanjaya-Putra D. Podoplanin is Responsible for the Distinct Blood and Lymphatic Capillaries. Cell Mol Bioeng 2022; 15:467-478. [PMID: 36444348 PMCID: PMC9700554 DOI: 10.1007/s12195-022-00730-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/21/2022] [Indexed: 11/03/2022] Open
Abstract
Abstract
Introduction
Controlling the formation of blood and lymphatic vasculatures is crucial for engineered tissues. Although the lymphatic vessels originate from embryonic blood vessels, the two retain functional and physiological differences even as they develop in the vicinity of each other. This suggests that there is a previously unknown molecular mechanism by which blood (BECs) and lymphatic endothelial cells (LECs) recognize each other and coordinate to generate distinct capillary networks.
Methods
We utilized Matrigel and fibrin assays to determine how cord-like structures (CLS) can be controlled by altering LEC and BEC identity through podoplanin (PDPN) and folliculin (FLCN) expressions. We generated BECΔFLCN and LECΔPDPN, and observed cell migration to characterize loss lymphatic and blood characteristics due to respective knockouts.
Results
We observed that LECs and BECs form distinct CLS in Matrigel and fibrin gels despite being cultured in close proximity with each other. We confirmed that the LECs and BECs do not recognize each other through paracrine signaling, as proliferation and migration of both cells were unaffected by paracrine signals. On the other hand, we found PDPN to be the key surface protein that is responsible for LEC-BEC recognition, and LECs lacking PDPN became pseudo-BECs and vice versa. We also found that FLCN maintains BEC identity through downregulation of PDPN.
Conclusions
Overall, these observations reveal a new molecular pathway through which LECs and BECs form distinct CLS through physical contact by PDPN which in turn is regulated by FLCN, which has important implications toward designing functional engineered tissues.
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26
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Kostyak JC, Mauri B, Dangelmaier C, Vari HR, Patel A, Wright M, Reddy H, Tsygankov AY, Kunapuli SP. Phosphorylation on Syk Y342 is important for both ITAM and hemITAM signaling in platelets. J Biol Chem 2022; 298:102189. [PMID: 35753354 PMCID: PMC9287148 DOI: 10.1016/j.jbc.2022.102189] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 11/29/2022] Open
Abstract
Immune cells express receptors bearing an immune tyrosine activation motif (ITAM) containing two YXXL motifs or hemITAMs containing only one YXXL motif. Phosphorylation of the ITAM/hemITAM is mediated by Src family kinases allowing for the binding and activation of spleen tyrosine kinase (Syk). It is believed that Syk must be phosphorylated on tyrosine residues for activation, and Tyr342, а conserved tyrosine in the interdomain B region, has been shown to be critical for regulating Syk in FcεR1-activated mast cells. Syk is a key mediator of signaling pathways downstream of several platelet pathways including the ITAM bearing glycoprotein VI (GPVI)/Fc receptor gamma chain collagen receptor and the hemITAM containing C-type lectin-like receptor-2 (CLEC-2). Since platelet activation is a crucial step in both hemostasis and thrombosis, we evaluated the importance of Syk Y342 in these processes by producing an Syk Y342F knock-in mouse. When using a CLEC-2 antibody as an agonist, reduced aggregation and secretion were observed in Syk Y342F mouse platelets when compared with control mouse platelets. Platelet reactivity was also reduced in response to the GPVI agonist collagen-related peptide. Signaling initiated by either GPVI or CLEC-2 was also greatly inhibited, including Syk Y519/520 phosphorylation. Hemostasis, as measured by tail bleeding time, was not altered in Syk Y342F mice, but thrombus formation in response to FeCl3 injury was prolonged in Syk Y342F mice. These data demonstrate that phosphorylation of Y342 on Syk following stimulation of either GPVI or CLEC-2 receptors is important for the ability of Syk to transduce a signal.
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Affiliation(s)
- John C Kostyak
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Benjamin Mauri
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Carol Dangelmaier
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Hymavathi Reddy Vari
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Akruti Patel
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Monica Wright
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Haritha Reddy
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Alexander Y Tsygankov
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Satya P Kunapuli
- Sol Sherry Thrombosis Research Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.
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27
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Zhang Z, Zhang N, Yu J, Xu W, Gao J, Lv X, Wen Z. The Role of Podoplanin in the Immune System and Inflammation. J Inflamm Res 2022; 15:3561-3572. [PMID: 35747250 PMCID: PMC9212786 DOI: 10.2147/jir.s366620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Podoplanin is a small cell-surface mucin-like glycoprotein that participates in multiple physiological and pathological processes. Podoplanin exerts an important function in the immune response and is upregulated in fibroblasts, macrophages, T helper cells, and epithelial cells during inflammation. Herein, we summarize the latest knowledge on the functional expression of podoplanin in the immune system and review the contribution of podoplanin to several inflammatory diseases. Furthermore, we discuss podoplanin as a novel therapeutic target for various inflammatory diseases.
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Affiliation(s)
- Zhiyuan Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Nan Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Jing Yu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Wenting Xu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Jiameng Gao
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Zongmei Wen
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
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28
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Le Chapelain O, Ho-Tin-Noé B. Intratumoral Platelets: Harmful or Incidental Bystanders of the Tumor Microenvironment? Cancers (Basel) 2022; 14:cancers14092192. [PMID: 35565321 PMCID: PMC9105443 DOI: 10.3390/cancers14092192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The tumor microenvironment (TME) is the complex and heterogenous ecosystem of solid tumors known to influence their growth and their progression. Besides tumor cells, the TME comprises a variety of host-derived cell types, ranging from endothelial cells to fibroblasts and immune cells. Clinical and experimental data are converging to indicate that platelets, originally known for their fundamental hemostatic function, also participate in tumor development and shaping of the TME. Considering the abundance of antiplatelet drugs, understanding if and how platelets contribute to the TME may lead to new therapeutic tools for improved cancer prevention and treatments. Abstract The tumor microenvironment (TME) has gained considerable interest because of its decisive impact on cancer progression, response to treatment, and disease recurrence. The TME can favor the proliferation, dissemination, and immune evasion of cancer cells. Likewise, there is accumulating evidence that intratumoral platelets could favor the development and aggressiveness of solid tumors, notably by influencing tumor cell phenotype and shaping the vascular and immune TME components. Yet, in contrast to other tumor-associated cell types like macrophages and fibroblasts, platelets are still often overlooked as components of the TME. This might be due, in part, to a deficit in investigating and reporting the presence of platelets in the TME and its relationships with cancer characteristics. This review summarizes available evidence from clinical and animal studies supporting the notion that tumor-associated platelets are not incidental bystanders but instead integral and active components of the TME. A particular emphasis is given to the description of intratumoral platelets, as well as to the functional consequences and possible mechanisms of intratumoral platelet accumulation.
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29
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Dangelmaier C, Vari HR, Wright M, Kostyak JC, Kunapuli SP. Clustering extent-dependent differential signaling by CLEC-2 receptors in platelets. Res Pract Thromb Haemost 2022; 6:e12710. [PMID: 35573643 PMCID: PMC9074038 DOI: 10.1002/rth2.12710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/08/2022] [Indexed: 11/12/2022] Open
Abstract
Background C-type lectin receptor family members play a role in many cells including platelets, where they are crucial in the separation of lymphatic and blood vessels during development. The C-type lectin-like receptor 2 (CLEC-2) receptor contains the canonical intracellular hemITAM motif through which it signals to activate Syk. Objectives One proposed hypothesis for signaling cascade is that Syk bridges two receptors through phosphorylated hemITAM motifs. We demonstrated that the phosphorylated hemITAM stimulates PI3 kinase/Btk pathways to activate Syk. To address this controversy, we used a CLEC-2 selective agonist and studied the role of Btk in platelet activation. Results and Conclusions Platelet activation and downstream signaling were abolished in murine and human platelets in the presence of the Btk inhibitors ibrutinib or acalabrutinib when a low concentration of a CLEC-2 antibody was used to crosslink CLEC-2 receptors. This inhibition was overcome by increasing concentrations of the CLEC-2 antibody. Similar results were obtained in X-linked immunodeficient mouse platelets, with an inactivating mutation in Btk or in Lyn null platelets. We conclude that at low crosslinking conditions of CLEC-2, Btk plays an important role in the activation of Syk, but at higher crosslinking conditions their role becomes less important and other mechanisms take over to activate Syk.
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Affiliation(s)
- Carol Dangelmaier
- Sol Sherry Thrombosis Research Center Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA
| | - Hymavathi Reddy Vari
- Sol Sherry Thrombosis Research Center Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA
| | - Monica Wright
- Sol Sherry Thrombosis Research Center Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA
| | - John C Kostyak
- Sol Sherry Thrombosis Research Center Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA
| | - Satya P Kunapuli
- Sol Sherry Thrombosis Research Center Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA
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30
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Haji S, Ito T, Guenther C, Nakano M, Shimizu T, Mori D, Chiba Y, Tanaka M, Mishra SK, Willment JA, Brown GD, Nagae M, Yamasaki S. Human Dectin-1 is O-glycosylated and serves as a ligand for C-type lectin receptor CLEC-2. eLife 2022; 11:83037. [PMID: 36479973 PMCID: PMC9788829 DOI: 10.7554/elife.83037] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022] Open
Abstract
C-type lectin receptors (CLRs) elicit immune responses upon recognition of glycoconjugates present on pathogens and self-components. While Dectin-1 is the best-characterized CLR recognizing β-glucan on pathogens, the endogenous targets of Dectin-1 are not fully understood. Herein, we report that human Dectin-1 is a ligand for CLEC-2, another CLR expressed on platelets. Biochemical analyses revealed that Dectin-1 is a mucin-like protein as its stalk region is highly O-glycosylated. A sialylated core 1 glycan attached to the EDxxT motif of human Dectin-1, which is absent in mouse Dectin-1, provides a ligand moiety for CLEC-2. Strikingly, the expression of human Dectin-1 in mice rescued the lethality and lymphatic defect resulting from a deficiency of Podoplanin, a known CLEC-2 ligand. This finding is the first example of an innate immune receptor also functioning as a physiological ligand to regulate ontogeny upon glycosylation.
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Affiliation(s)
- Shojiro Haji
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Taiki Ito
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Carla Guenther
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Miyako Nakano
- Graduate School of Integrated Sciences for Life, Hiroshima UniversityHiroshimaJapan
| | - Takashi Shimizu
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Daiki Mori
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Yasunori Chiba
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)TsukubaJapan
| | - Masato Tanaka
- Laboratory of Immune Regulation School of Life Sciences, Tokyo University of Pharmacy and Life SciencesHachiojiJapan
| | - Sushil K Mishra
- The Glycoscience Group, National University of Ireland, GalwayGalwayIreland
| | - Janet A Willment
- Medical Research Council Centre for Medical Mycology, University of ExeterExeterUnited Kingdom
| | - Gordon D Brown
- Medical Research Council Centre for Medical Mycology, University of ExeterExeterUnited Kingdom
| | - Masamichi Nagae
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Sho Yamasaki
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan,Center for Infectious Disease Education and Research (CiDER), Osaka UniversityOsakaJapan,Division of Molecular Design, Research Center for Systems Immunology, Medical Institute of Bioregulation, Kyushu UniversityFukuokaJapan
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31
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-62v2kivtk' or 159=(select 159 from pg_sleep(9))--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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32
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6w8jpumgz'); waitfor delay '0:0:18' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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33
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-675tomkjw'); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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34
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1); waitfor delay '0:0:18' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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35
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6inyod6yy'); waitfor delay '0:0:0' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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36
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6' and 2*3*8=6*8 and 'q4ng'='q4ng] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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37
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6uo9qdmbo' or 900=(select 900 from pg_sleep(15))--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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38
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6xjcyx5xp'; waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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39
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6kliwx55t'; waitfor delay '0:0:0' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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40
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-60"xor(if(now()=sysdate(),sleep(15),0))xor"z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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41
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1 waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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42
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6" and 2*3*8=6*8 and "1plv"="1plv] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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43
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-60'xor(if(now()=sysdate(),sleep(15),0))xor'z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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44
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6jpd2wffe'); waitfor delay '0:0:9' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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45
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6xkcvwszk'); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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46
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 PMCID: PMC8371859 DOI: 10.1186/s41232-021-00175-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/05/2023] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn’s disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer’s disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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47
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1; waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6'||'] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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49
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-60"xor(if(now()=sysdate(),sleep(9),0))xor"z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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50
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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