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Støy S, D'Alessio S, Sandahl TD, Dige A, Kjølbye AL, Jorgensen R, Danese S, van de Bunt M. Lipidated IL-22 Alone or Combined with Immunomodulatory Agents Improves Disease Endpoints and Promotes Mucosal Healing in a Mouse Model of Chronic Dextran Sodium Sulfate-Induced Colitis. Dig Dis Sci 2025:10.1007/s10620-025-09007-w. [PMID: 40138118 DOI: 10.1007/s10620-025-09007-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND IL-22 facilitates mucosal healing by directly inducing epithelial regeneration and barrier integrity, which is essential for achieving remission and thereby treating inflammatory bowel disease. AIMS Here, we evaluated efficacy of a novel lipidated IL-22 alone and in combination with immunomodulatory agents in addressing chronic dextran sodium sulfate (DSS)-induced colitis in mice and demonstrated action of IL-22 on mucosal healing. METHODS Mice were treated with DSS, followed by various doses of lipidated IL-22, anti-TNF antibody, fingolimod, or anti-mouse α4β7 integrin antibody. Additionally, gene expression was determined in colonic biopsies from ulcerative colitis patients to assess effects of IL-22 stimulation. RESULTS Lipidated IL-22 significantly improved all aspects of chronic DSS-induced colitis in mice, with dose-dependent efficacy. Combinations of a range of immunomodulatory agents with lipidated IL-22 showed further additive reductions in disease activity, significantly greater than those of monotherapies. Immunohistochemistry revealed that lipidated IL-22 increased epithelial cell proliferation and reduced CD3+ T-cell infiltration, indicating enhanced mucosal healing. This was further supported gene expression data from colonic biopsies from ulcerative colitis patients after IL-22 stimulation. CONCLUSIONS Given the challenges in achieving long-term remission in IBD due to inflammation and mucosal damage, lipidated IL-22 presents a promising treatment option that directly promotes mucosal healing, unlike traditional immunomodulatory therapies.
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Affiliation(s)
- Sidsel Støy
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Anders Dige
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | | | - Silvio Danese
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Hospital, Milan, Italy
- IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
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2
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Razavi MS, Munn LL, Padera TP. Mechanics of Lymphatic Pumping and Lymphatic Function. Cold Spring Harb Perspect Med 2025; 15:a041171. [PMID: 38692743 PMCID: PMC11875091 DOI: 10.1101/cshperspect.a041171] [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: 05/03/2024]
Abstract
The lymphatic system plays a crucial role in maintaining tissue fluid balance, immune surveillance, and the transport of lipids and macromolecules. Lymph is absorbed by initial lymphatics and then driven through lymph nodes and to the blood circulation by the contraction of collecting lymphatic vessels. Intraluminal valves in collecting lymphatic vessels ensure the unidirectional flow of lymph centrally. The lymphatic muscle cells that invest in collecting lymphatic vessels impart energy to propel lymph against hydrostatic pressure gradients and gravity. A variety of mechanical and biochemical stimuli modulate the contractile activity of lymphatic vessels. This review focuses on the recent advances in our understanding of the mechanisms involved in regulating and collecting lymphatic vessel pumping in normal tissues and the association between lymphatic pumping, infection, inflammatory disease states, and lymphedema.
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Affiliation(s)
- Mohammad S Razavi
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Lance L Munn
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Timothy P Padera
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
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Katoh D, Senga Y, Mizutani K, Maruyama K, Yamakawa D, Yamamuro T, Hiroe M, Yamanaka K, Sudo A, Katayama N, Yoshida T, Imanaka-Yoshida K. Negative regulation of lymphangiogenesis by Tenascin-C delays the resolution of inflammation. iScience 2025; 28:111756. [PMID: 39925433 PMCID: PMC11803235 DOI: 10.1016/j.isci.2025.111756] [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: 04/30/2024] [Revised: 10/08/2024] [Accepted: 12/23/2024] [Indexed: 02/11/2025] Open
Abstract
Lymphatic vessels are required for the clearance of excess fluid and immune cells from inflamed tissue, making the regulation of lymphangiogenesis an important area of research. Although the positive regulatory mechanisms of lymphangiogenesis are well known, the negative regulatory mechanisms observed during inflammation remain unclear. Here, we identify tenascin-C (TNC) as a spatiotemporal negative regulator of lymphangiogenesis during inflammation. We found an inverse correlation between lymphangiogenesis and TNC expression in a mouse lymphedema model. Genetic deletion of Tnc promotes lymphangiogenesis and improves lymphatic drainage function, thereby accelerating the resolution of inflammation. Conversely, the exogenous addition of TNC suppresses lymphangiogenesis and prolongs inflammation. TNC inhibits the proliferation and promotes apoptosis of lymphatic endothelial cells. Mechanistically, TNC facilitates integrin αvβ1 heterodimer formation, leading to the activation of non-canonical (TAK1/p38MAPK/ATF-2) TGFβ signaling to suppress lymphangiogenesis. Our study highlights the importance of negative regulation of lymphangiogenesis in modulating immune responses.
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Affiliation(s)
- Daisuke Katoh
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Yoshiyuki Senga
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kento Mizutani
- Department of Dermatology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kazuaki Maruyama
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Daishi Yamakawa
- Department of Physiology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Tadashi Yamamuro
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Michiaki Hiroe
- Department of Cardiology, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
| | - Keiichi Yamanaka
- Department of Dermatology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Akihiro Sudo
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Naoyuki Katayama
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Toshimichi Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kyoko Imanaka-Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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Xu X, Ying H, Wang X, Hong W, Zhang M. Identification of Angiogenesis-Related Gene Signatures and Prediction of Potential Therapeutic Targets in Ulcerative Colitis Using Integrated Bioinformatics. J Inflamm Res 2024; 17:11699-11717. [PMID: 39741751 PMCID: PMC11687120 DOI: 10.2147/jir.s478880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/10/2024] [Indexed: 01/03/2025] Open
Abstract
Objective This study aims to clarify angiogenesis mechanisms in ulcerative colitis and identify potential therapeutic targets. Methods The Gene Expression Omnibus (GEO) database was used to obtain expression profiles and clinical data for UC and healthy colon tissues. Angiogenesis-related gene sets were acquired from GeneCards. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified UC-associated hub genes. The CIBERSORT algorithm assessed immune cell infiltration. Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to determine biological mechanisms. External datasets were utilized to validate and characterize the angiogenesis-related genes in relation to biological agents. Additionally, an ulcerative colitis mouse model was constructed to verify the key genes' expression using real-time quantitative PCR. To predict potential therapeutic agents, we used the DGIdb database. Molecular docking modeled small molecule binding conformations to key gene targets. Results This study identified 1,247 DEGs enriched in inflammatory/immune pathways from UC and healthy colon samples. WGCNA indicated the black and light cyan modules were most relevant. Intersecting these with 89 angiogenesis genes revealed 5 UC-associated hub genes (pdgfrb, vegfc, angpt2, tnc, hgf). Validation via ROC analysis, differential expression, and a mouse model confirmed upregulation, supporting their potential as UC diagnostic biomarkers. Bioinformatics approaches like protein-protein interaction, enrichment analysis, and GSEA revealed involvement in PDGFR and PI3K-Akt signaling pathways. CIBERSORT analysis of immune cell infiltration showed positive correlations between the key genes and various immune cells, especially neutrophils, highlighting angiogenesis-inflammation interplay in UC. A ceRNA network was constructed. Drug prediction and molecular docking revealed potential UC therapies like sunitinib and imatinib targeting angiogenesis. Conclusion This study identified and validated five angiogenesis-related genes (pdgfrb, vegfc, angpt2, tnc, hgf) that may serve as diagnostic biomarkers and drug targets for UC.
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Affiliation(s)
- Xijuan Xu
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Hongan Ying
- Department of Geriatrics, Taizhou First People’s Hospital, Taizhou, People’s Republic of China
| | - Xiaozhi Wang
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Weiwen Hong
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Meng Zhang
- Department of General Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
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Shu W, Wang Y, Chen M, Zhu X, Wang F, Chen C, Du P, Bartolomucci A, Su X, Wang X. Extracellular vesicles derived from creeping fat stem cells promote lymphatic function and restrain inflammation of Crohn's disease. Clin Transl Med 2024; 14:e70086. [PMID: 39623906 PMCID: PMC11612264 DOI: 10.1002/ctm2.70086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/18/2024] [Accepted: 10/31/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Crohn's disease (CD) is a chronic inflammatory disease in the intestinal tract. Mesenteric fat wrapping and thickening, or creeping fat (CrF), is a typical characteristic of CD and it involves lymphangiogenesis and altered lymphatic function. By releasing extracellular vesicles (EVs), adipose tissue-derived stem cells (ADSCs) can regulate their adjacent cells. However, the regulating roles of ADSC-EVs in CrF (CrF-EVs) in CD, especially in modulating lymphatic function and mitigating the progression of mesenteritis and colitis, remains elusive. METHODS To evaluate the regulative roles of CrF-EVs on lymphatic functions, in vitro assays were performed using human lymphatic endothelial cells (HLECs). Next, Interleukin 10 knock-out (Il-10-/-) mice were used to assess the biological functions of CrF-EVs in spontaneous mesenteritis and colitis. Moreover, tissue and serum from various cohorts of CD patients were used to determine the prognostic value of miR-132-3p. RESULTS CrF-EVs significantly attenuated spontaneous mesenteritis and colitis in Il-10-/- mice via promoting lymphangiogenesis and lymphatic drainage. Using high-throughput sequencing, we demonstrated that CrF-EVs significantly increased HLEC proliferation, migration, tube formation and CCL-21 production in a miR-132-3p/RASA1/ERK1/2 axis-dependent manner. Accordingly, upregulated miR-132-3p was observed in patient CrF, positively correlated with lymphangiogenesis while negatively correlated with inflammatory factors (tumour necrosis factor-α and IL-6) level. Moreover, serum miR-132-3p demonstrated a positive correlation with disease activity. CONCLUSIONS EVs derived from CrF ADSCs, containing elevated levels of miR-132-3p, could promote lymphatic function and restrain inflammation of CD. Our results provide a novel insight into the role of mesenteric lymphatics in CD progression and reveal a new potential therapeutic. KEY POINTS Extracellular vesicles (EVs) of creeping fat (CrF) derived adipose stem cells effectively attenuate chronic mesenteritis and colitis in Crohn's disease (CD). The lymphatic vessels play an important role in disease development of CD and their functions are improved by CrF-EV-miR-132-3p through RASA1/ERK1/2 signaling. MiR-132-3p expression is upregulated in CrF and serum of CD patients, and tightly linked with inflammation and disease activity.
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Affiliation(s)
- Weigang Shu
- Department of GastroenterologyShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Yongheng Wang
- Department of GastroenterologyShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Mengfan Chen
- Department of GastroenterologyShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Xiaoli Zhu
- Department of GastroenterologyShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Fangtao Wang
- Department of General SurgeryShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Chunqiu Chen
- Department of General SurgeryShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Peng Du
- Department of Colorectal SurgeryXinhua Hospital, Shanghai Jiaotong UniversitySchool of MedicineShanghaiChina
| | - Alexandra Bartolomucci
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealCanada
| | - Xin Su
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealCanada
| | - Xiaolei Wang
- Department of GastroenterologyShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghaiChina
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Ji RC. The emerging importance of lymphangiogenesis in aging and aging-associated diseases. Mech Ageing Dev 2024; 221:111975. [PMID: 39089499 DOI: 10.1016/j.mad.2024.111975] [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: 05/15/2024] [Revised: 07/17/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging.
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Affiliation(s)
- Rui-Cheng Ji
- Faculty of Welfare and Health Science, Oita University, Oita 870-1192, Japan.
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Duan M, Coffey JC, Li Y. Mesenteric-based surgery for Crohn's disease: evidence and perspectives. Surgery 2024; 176:51-59. [PMID: 38594102 DOI: 10.1016/j.surg.2024.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 01/20/2024] [Accepted: 02/26/2024] [Indexed: 04/11/2024]
Abstract
Postoperative anastomotic recurrence of Crohn's disease is challenging and can lead to symptom recurrence and further surgery. The mesenteric pole of the intestine is the initial site of macroscopic anastomotic recurrence, and the mesentery may play an important role in recurrence after surgical resection. Therefore, "mesenteric-based surgery" has gained increasing attention by clinicians. However, the role of mesentery in the postoperative recurrence remains controversial. This review will examine mesenteric changes in Crohn's disease, proposed roles for mesentery in disease progression, and the potential for mesenteric-based surgery in the surgical management of Crohn disease.
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Affiliation(s)
- Ming Duan
- Center for Inflammatory Bowel Diseases, Department of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, China
| | - J Calvin Coffey
- Department of Surgery, University of Limerick Hospital Group, and School of Medicine, University of Limerick, Limerick, Ireland.
| | - Yi Li
- Center for Inflammatory Bowel Diseases, Department of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, China
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Shu W, Wang Y, Deji Z, Li C, Chen C, Ding W, Du P, Wang X. Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn's disease. Inflamm Res 2024; 73:1157-1172. [PMID: 38713235 DOI: 10.1007/s00011-024-01889-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/31/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown. METHODS CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting. RESULTS CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs' barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF. CONCLUSIONS Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.
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Affiliation(s)
- Weigang Shu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Yongheng Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Zhuoma Deji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Chuanding Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Chunqiu Chen
- Center for Difficult and Complicated Abdominal Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Wenjun Ding
- Department of Colorectal Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Xiaolei Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
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Lasagni S, Critelli RM, Milosa F, Saltini D, Schepis F, Romanzi A, Dituri F, Serino G, Di Marco L, Pivetti A, Scianò F, Giannelli G, Villa E. Differential Impact of Tumor Endothelial Angiopoietin-2 and Podoplanin in Lymphatic Endothelial Cells on HCC Outcomes with Tyrosine Kinase Inhibitor Treatment According to Sex. Biomedicines 2024; 12:1424. [PMID: 39061998 PMCID: PMC11273995 DOI: 10.3390/biomedicines12071424] [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: 05/21/2024] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are the only potential treatment option. Despite extensive research, predictors of response to these therapies remain elusive. This study aimed to analyze the biological and histopathological characteristics of HCC patients treated with TKIs, focusing on angiogenesis and lymphangiogenesis. Immunohistochemistry quantified the expression of angiopoietin-2 (Ang2), lymphatic endothelial cells (LEC) podoplanin, and C-type Lectin Domain Family 2 (CLEC-2), key factors in neoangiogenesis and lymphangiogenesis. An increased expression of endothelial Ang2 and LEC podoplanin predicted a lower risk of metastasis. Female patients had significantly longer overall survival and survival on TKIs, associated with higher tumor expression of endothelial Ang2 and LEC podoplanin. Moreover, LEC podoplanin expression and a longer time on TKIs were independently correlated with improved survival on TKI therapy at Cox regression analysis. These findings suggest that endothelial Ang2 and LEC podoplanin could be potential biomarkers for predicting treatment outcomes and guiding therapeutic strategies in HCC patients treated with TKIs.
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Affiliation(s)
- Simone Lasagni
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
- Clinical and Experimental Medicine Program, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy;
| | - Rosina Maria Critelli
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
| | - Fabiola Milosa
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
| | - Dario Saltini
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
| | - Filippo Schepis
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
| | - Adriana Romanzi
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
- Clinical and Experimental Medicine Program, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy;
| | - Francesco Dituri
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (F.D.); (G.S.); (G.G.)
| | - Grazia Serino
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (F.D.); (G.S.); (G.G.)
| | - Lorenza Di Marco
- Clinical and Experimental Medicine Program, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy;
| | - Alessandra Pivetti
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy; (A.P.); (F.S.)
| | - Filippo Scianò
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy; (A.P.); (F.S.)
| | - Gianluigi Giannelli
- National Institute of Gastroenterology “IRCCS Saverio de Bellis”, Research Hospital, 70013 Castellana Grotte, Italy; (F.D.); (G.S.); (G.G.)
| | - Erica Villa
- Gastroenterology Unit, Chimomo Department, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.L.); (R.M.C.); (F.M.); (D.S.); (F.S.); (A.R.)
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Morotti F, Aversa S, Barbieri F, Risso FM. Delayed episode of necrotising enterocolitis in an ex-preterm infant after intravitreal administration of low-dose ranibizumab for the treatment of retinopathy of prematurity. BMJ Case Rep 2024; 17:e259537. [PMID: 38839401 DOI: 10.1136/bcr-2023-259537] [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: 06/07/2024] Open
Abstract
Retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC) are complications of prematurity. Despite being quite different in terms of incidence, pathogenesis and consequences, both share a pathogenic role of aberrant vascularisation: increased in ROP, deficient for NEC. Current therapy for ROP includes the use of anti-vascular endothelial growth factor (anti-VEGF) agents, which are able to interrupt retinal hypervascularity. Despite being delivered intravitreously, anti-VEGF used in ROP can be absorbed into circulation and exert systemic effects. We present here a case of an ex-27 weeks gestational age infant, presenting multiple NEC risk factors, treated at 2 months of age with low-dose ranibizumab, who developed a large bowel NEC episode in the first week after treatment. We believe that this further report of an association between anti-VEGF agents and NEC could be interesting for the identification of children at risk of severe adverse events and stimulating further research on the topic.
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Affiliation(s)
- Francesco Morotti
- Neonatal Intensive Care Unit, Children's Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Salvatore Aversa
- Neonatal Intensive Care Unit, Children's Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Fabiana Barbieri
- Neonatal Intensive Care Unit, Children's Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Francesco Maria Risso
- Neonatal Intensive Care Unit, Children's Hospital, ASST Spedali Civili di Brescia, Brescia, Italy
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Zhao D, Cheng L, Lu F, Zhang X, Ying J, Wei X, Cao F, Ran C, Zheng G, Liu G, Yi P, Wang H, Song L, Wu B, Liu L, Li L, Wang X, Li J. Design, fabrication and clinical characterization of additively manufactured tantalum hip joint prosthesis. Regen Biomater 2024; 11:rbae057. [PMID: 38854680 PMCID: PMC11162747 DOI: 10.1093/rb/rbae057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 05/04/2024] [Indexed: 06/11/2024] Open
Abstract
The joint prosthesis plays a vital role in the outcome of total hip arthroplasty. The key factors that determine the performance of joint prostheses are the materials used and the structural design of the prosthesis. This study aimed to fabricate a porous tantalum (Ta) hip prosthesis using selective laser melting (SLM) technology. The feasibility of SLM Ta use in hip prosthesis was verified by studying its chemical composition, metallographic structure and mechanical properties. In vitro experiments proved that SLM Ta exhibited better biological activities in promoting osteogenesis and inhibiting inflammation than SLM Ti6Al4V. Then, the topological optimization design of the femoral stem of the SLM Ta hip prosthesis was carried out by finite element simulation, and the fatigue performance of the optimized prosthesis was tested to verify the biomechanical safety of the prosthesis. A porous Ta acetabulum cup was also designed and fabricated using SLM. Its mechanical properties were then studied. Finally, clinical trials were conducted to verify the clinical efficacy of the SLM Ta hip prosthesis. The porous structure could reduce the weight of the prosthesis and stress shielding and avoid bone resorption around the prosthesis. In addition, anti-infection drugs can also be loaded into the pores for infection treatment. The acetabular cup can be custom-designed based on the severity of bone loss on the acetabular side, and the integrated acetabular cup can repair the acetabular bone defect while achieving the function of the acetabular cup.
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Affiliation(s)
- Dewei Zhao
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Liangliang Cheng
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Faqiang Lu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Xiuzhi Zhang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Jiawei Ying
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Xiaowei Wei
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Fang Cao
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Chunxiao Ran
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Guoshuang Zheng
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Ge Liu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Pinqiao Yi
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Haiyao Wang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Liqun Song
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Bin Wu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Lingpeng Liu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Lu Li
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Xiaohu Wang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
| | - Junlei Li
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China
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12
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Karakousi T, Mudianto T, Lund AW. Lymphatic vessels in the age of cancer immunotherapy. Nat Rev Cancer 2024; 24:363-381. [PMID: 38605228 DOI: 10.1038/s41568-024-00681-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/27/2024] [Indexed: 04/13/2024]
Abstract
Lymphatic transport maintains homeostatic health and is necessary for immune surveillance, and yet lymphatic growth is often associated with solid tumour development and dissemination. Although tumour-associated lymphatic remodelling and growth were initially presumed to simply expand a passive route for regional metastasis, emerging research puts lymphatic vessels and their active transport at the interface of metastasis, tumour-associated inflammation and systemic immune surveillance. Here, we discuss active mechanisms through which lymphatic vessels shape their transport function to influence peripheral tissue immunity and the current understanding of how tumour-associated lymphatic vessels may both augment and disrupt antitumour immune surveillance. We end by looking forward to emerging areas of interest in the field of cancer immunotherapy in which lymphatic vessels and their transport function are likely key players: the formation of tertiary lymphoid structures, immune surveillance in the central nervous system, the microbiome, obesity and ageing. The lessons learnt support a working framework that defines the lymphatic system as a key determinant of both local and systemic inflammatory networks and thereby a crucial player in the response to cancer immunotherapy.
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Affiliation(s)
- Triantafyllia Karakousi
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA
| | - Tenny Mudianto
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA
| | - Amanda W Lund
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
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13
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Zhang Y, Wu Z, Zhao Q, Liu Y, Huang Q, Zhang M, Li S, Wang D, Li N, Chi Y, Liu Y. Mesenteric Lymphatic B Cells Migrate to the Intestine and Aggravate DSS-Induced Colitis via the CXCR5-CXCL13 Axis. BIOLOGY 2024; 13:322. [PMID: 38785804 PMCID: PMC11117591 DOI: 10.3390/biology13050322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/29/2024] [Accepted: 05/02/2024] [Indexed: 05/25/2024]
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is still unknown. Mesenteric lymphatics (MLs), which are closely related to the intestine in both anatomy and physiology, have been suggested to be involved in IBD. In the present study, we aim to investigate the effects of ML immune cells on IBD and explore the potential associated mechanisms. Acute colitis was induced in rats using dextran sulfate sodium salt (DSS). Mesenteric lymphangiogenesis, ML stenosis, and dilation were observed, with an increased proportion of MLB cells in DSS-induced colitis rats. The adoptive transfer of B cells isolated from ML (MLB) was employed to investigate their effects on colitis. MLB cells derived from DSS-induced colitis rats exhibited a higher propensity to migrate to the intestine. The proportion of colonic T cells was altered, along with the aggravated colitis induced by the adoptive transfer of MLB cells derived from DSS-induced colitis rats. RNA sequencing revealed increased Cxcr5 expression in MLB cells from colitis rats, while real-time PCR indicated an upregulation of its ligand Cxcl13 in the colon of colitis rats. These findings suggest that MLB cells may migrate to the intestine and aggravate colitis. In summary, colonic T cells respond to MLB cells from colitis rats, and MLB cells aggravate DSS-induced colitis via the CXCR5-CXCL13 axis.
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Affiliation(s)
- Yu Zhang
- Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China; (Y.Z.); (Z.W.); (Q.Z.)
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing 100044, China
| | - Zhe Wu
- Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China; (Y.Z.); (Z.W.); (Q.Z.)
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing 100044, China
| | - Qinghe Zhao
- Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China; (Y.Z.); (Z.W.); (Q.Z.)
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China; (D.W.); (N.L.)
| | - Yaming Liu
- Department of Gastroenterology and Hepatology, Xiamen University Zhongshan Hospital, Xiamen 361001, China;
| | - Qing Huang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China;
| | - Menglei Zhang
- Department of Animal Laboratory, Peking University People’s Hospital, Beijing 100044, China; (M.Z.); (S.L.)
| | - Shuolei Li
- Department of Animal Laboratory, Peking University People’s Hospital, Beijing 100044, China; (M.Z.); (S.L.)
| | - Di Wang
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China; (D.W.); (N.L.)
| | - Na Li
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China; (D.W.); (N.L.)
| | - Yujing Chi
- Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China; (Y.Z.); (Z.W.); (Q.Z.)
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China; (D.W.); (N.L.)
| | - Yulan Liu
- Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China; (Y.Z.); (Z.W.); (Q.Z.)
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing 100044, China
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14
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Lin H, Cao B. Circulating VEGF and inflammatory bowel disease: a bidirectional mendelian randomization. Front Genet 2024; 15:1282471. [PMID: 38699232 PMCID: PMC11063361 DOI: 10.3389/fgene.2024.1282471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 03/18/2024] [Indexed: 05/05/2024] Open
Abstract
Introduction: Prior observational studies have suggested an association between circulating vascular endothelial growth factor (VEGF) levels and inflammatory bowel disease (IBD). This study sought to demonstrate the directionality of the association between circulating VEGF and particular forms of IBD as well as if there is a causal relationship between them. Methods: We collected summary data from relevant genome-wide association studies (GWASs) to assess the validity of causality, and a two-sample bidirectional Mendelian randomization (MR) study and sensitivity testing were performed to assess the causal relationship between circulating VEGF and IBD risk, including Crohn's disease and ulcerative colitis. Results: Our findings revealed a direct causal link between circulating VEGF and Crohn's disease (b 0.195, se 0.078, p < 0.013). However, neither circulating VEGF nor ulcerative colitis were shown to be causally linked (p > 0.025), nor was there proof of a reverse causal relationship from IBD to VEGF. Discussion: In conclusion, circulating VEGF shows a cause-and-effect relationship with Crohn's disease.
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Affiliation(s)
| | - Bangwei Cao
- Cancer Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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15
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Liu Z, Liu K, Shi S, Chen X, Gu X, Wang W, Mao K, Yibulayi R, Wu W, Zeng L, Zhou W, Lin X, Zhang F, Lou B. Alkali injury-induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation. JCI Insight 2024; 9:e175479. [PMID: 38587075 PMCID: PMC11128208 DOI: 10.1172/jci.insight.175479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 02/14/2024] [Indexed: 04/09/2024] Open
Abstract
Inflammatory lymphangiogenesis is intimately linked to immune regulation and tissue homeostasis. However, current evidence has suggested that classic lymphatic vessels are physiologically absent in intraocular structures. Here, we show that neolymphatic vessels were induced in the iris after corneal alkali injury (CAI) in a VEGFR3-dependent manner. Cre-loxP-based lineage tracing revealed that these lymphatic endothelial cells (LECs) originate from existing Prox1+ lymphatic vessels. Notably, the ablation of iridial lymphangiogenesis via conditional deletion of VEGFR3 alleviated the ocular inflammatory response and pathological T cell infiltration. Our findings demonstrate that iridial neolymphatics actively participate in pathological immune responses following injury and suggest intraocular lymphangiogenesis as a valuable therapeutic target for the treatment of ocular inflammation.
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Affiliation(s)
- Zheng Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Keli Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Shunhua Shi
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Xun Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Xinyu Gu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Weifa Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Keli Mao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Rukeye Yibulayi
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Wanwen Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Lei Zeng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Weibin Zhou
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaofeng Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Feng Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Bingsheng Lou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
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16
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Aradi P, Kovács G, Kemecsei É, Molnár K, Sági SM, Horváth Z, Mehrara BJ, Kataru RP, Jakus Z. Lymphatic-Dependent Modulation of the Sensitization and Elicitation Phases of Contact Hypersensitivity. J Invest Dermatol 2024:S0022-202X(24)00261-6. [PMID: 38548256 DOI: 10.1016/j.jid.2024.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 02/17/2024] [Accepted: 03/01/2024] [Indexed: 05/26/2024]
Abstract
Allergic contact dermatitis is a common inflammatory skin disease comprising 2 phases. During sensitization, immune cells are activated by exposure to various allergens, whereas repeated antigen exposure induces local inflammation during elicitation. In this study, we utilized mouse models lacking lymphatics in different skin regions to characterize the role of lymphatics separately in the 2 phases, using contact hypersensitivity as a model of human allergic inflammatory skin diseases. Lymphatic-deficient mice exhibited no major difference to single antigen exposure compared to controls. However, mice lacking lymphatics in both phases displayed reduced inflammation after repeated antigen exposure. Similarly, diminished immune response was observed in mice lacking lymphatics only in sensitization, whereas the absence of lymphatics only in the elicitation phase resulted in a more pronounced inflammatory immune response. This exaggerated inflammation is driven by neutrophils impacting regulatory T cell number. Collectively, our results demonstrate that skin lymphatics play an important but distinct role in the 2 phases of contact hypersensitivity. During sensitization, lymphatics contribute to the development of the antigen-specific immunization, whereas in elicitation, they moderate the inflammatory response and leukocyte infiltration in a neutrophil-dependent manner. These findings underscore the need for novel therapeutic strategies targeting the lymphatics in the context of allergic skin diseases.
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Affiliation(s)
- Petra Aradi
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Gábor Kovács
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Éva Kemecsei
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Kornél Molnár
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Stella Márta Sági
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Zalán Horváth
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Babak J Mehrara
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Raghu P Kataru
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Zoltán Jakus
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
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17
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Kannan S, Rutkowski JM. VEGFR-3 signaling in macrophages: friend or foe in disease? Front Immunol 2024; 15:1349500. [PMID: 38464522 PMCID: PMC10921555 DOI: 10.3389/fimmu.2024.1349500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/01/2024] [Indexed: 03/12/2024] Open
Abstract
Lymphatic vessels have been increasingly appreciated in the context of immunology not only as passive conduits for immune and cancer cell transport but also as key in local tissue immunomodulation. Targeting lymphatic vessel growth and potential immune regulation often takes advantage of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling to manipulate lymphatic biology. A receptor tyrosine kinase, VEGFR-3, is highly expressed on lymphatic endothelial cells, and its signaling is key in lymphatic growth, development, and survival and, as a result, often considered to be "lymphatic-specific" in adults. A subset of immune cells, notably of the monocyte-derived lineage, have been identified to express VEGFR-3 in tissues from the lung to the gut and in conditions as varied as cancer and chronic kidney disease. These VEGFR-3+ macrophages are highly chemotactic toward the VEGFR-3 ligands VEGF-C and VEGF-D. VEGFR-3 signaling has also been implicated in dictating the plasticity of these cells from pro-inflammatory to anti-inflammatory phenotypes. Conversely, expression may potentially be transient during monocyte differentiation with unknown effects. Macrophages play critically important and varied roles in the onset and resolution of inflammation, tissue remodeling, and vasculogenesis: targeting lymphatic vessel growth and immunomodulation by manipulating VEGFR-3 signaling may thus impact macrophage biology and their impact on disease pathogenesis. This mini review highlights the studies and pathologies in which VEGFR-3+ macrophages have been specifically identified, as well as the activity and polarization changes that macrophage VEGFR-3 signaling may elicit, and affords some conclusions as to the importance of macrophage VEGFR-3 signaling in disease.
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Affiliation(s)
| | - Joseph M. Rutkowski
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, United States
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18
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Kovacs MA, Babcock IW, Royo Marco A, Sibley LA, Kelly AG, Harris TH. Vascular Endothelial Growth Factor-C Treatment Enhances Cerebrospinal Fluid Outflow during Toxoplasma gondii Brain Infection but Does Not Improve Cerebral Edema. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:225-237. [PMID: 38065361 PMCID: PMC10835445 DOI: 10.1016/j.ajpath.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 10/02/2023] [Accepted: 11/06/2023] [Indexed: 01/22/2024]
Abstract
Cerebral edema frequently develops in the setting of brain infection and can contribute to elevated intracranial pressure, a medical emergency. How excess fluid is cleared from the brain is not well understood. Previous studies have shown that interstitial fluid is transported out of the brain along perivascular channels that collect into the cerebrospinal fluid (CSF)-filled subarachnoid space. CSF is then removed from the central nervous system through venous and lymphatic routes. The current study tested the hypothesis that increasing lymphatic drainage of CSF would promote clearance of cerebral edema fluid during infection with the neurotropic parasite Toxoplasma gondii. Fluorescent microscopy and magnetic resonance imaging was used to show that C57BL/6 mice develop vasogenic edema 4 to 5 weeks after infection with T. gondii. Tracer experiments were used to evaluate how brain infection affects meningeal lymphatic function, which demonstrated a decreased rate in CSF outflow in T. gondii-infected mice. Next, mice were treated with a vascular endothelial growth factor (VEGF)-C-expressing viral vector, which induced meningeal lymphangiogenesis and improved CSF outflow in chronically infected mice. No difference in cerebral edema was observed between mice that received VEGF-C and those that rececived sham treatment. Therefore, although VEGF-C treatment can improve lymphatic outflow in mice infected with T. gondii, this effect does not lead to increased clearance of edema fluid from the brains of these mice.
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Affiliation(s)
- Michael A Kovacs
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia
| | - Isaac W Babcock
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia
| | - Ana Royo Marco
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia
| | - Lydia A Sibley
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia
| | - Abigail G Kelly
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia
| | - Tajie H Harris
- Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, Virginia.
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19
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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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Kuonqui K, Campbell AC, Sarker A, Roberts A, Pollack BL, Park HJ, Shin J, Brown S, Mehrara BJ, Kataru RP. Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease. Cells 2023; 13:68. [PMID: 38201272 PMCID: PMC10778007 DOI: 10.3390/cells13010068] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/20/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Babak J. Mehrara
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Raghu P. Kataru
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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21
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Wu Q, Meng W, Zhu B, Chen X, Fu J, Zhao C, Liu G, Luo X, Lv Y, Zhao W, Wang F, Hu S, Zhang S. VEGFC ameliorates salt-sensitive hypertension and hypertensive nephropathy by inhibiting NLRP3 inflammasome via activating VEGFR3-AMPK dependent autophagy pathway. Cell Mol Life Sci 2023; 80:327. [PMID: 37837447 PMCID: PMC11072217 DOI: 10.1007/s00018-023-04978-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/29/2023] [Accepted: 09/23/2023] [Indexed: 10/16/2023]
Abstract
Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury.
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Affiliation(s)
- Qiuwen Wu
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, China
| | - Wei Meng
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, China
| | - Bin Zhu
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, China
| | - Xi Chen
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
| | - Jiaxin Fu
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
| | - Chunyu Zhao
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
| | - Gang Liu
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xing Luo
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
| | - Ying Lv
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
| | - Wenqi Zhao
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Fan Wang
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China
| | - Sining Hu
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China.
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, China.
| | - Shuo Zhang
- Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China.
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, China.
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22
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Yang J, Guan X, He S, Ge L, Gao Q, Wu X. FTY720 attenuates acute colitis via colonic T cells reduction and inhibition of M1 macrophages polarization independent of CCR2-mediated monocytes input. Int Immunopharmacol 2023; 123:110731. [PMID: 37541109 DOI: 10.1016/j.intimp.2023.110731] [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: 05/20/2023] [Revised: 07/11/2023] [Accepted: 07/27/2023] [Indexed: 08/06/2023]
Abstract
Ulcerative colitis (UC) is a complex multifactorial disease, of which the exact etiology is not fully understood. The inappropriate aggressive inflammatory response is closely related to the disease progression of UC. FTY720 is a sphingosine-1-phosphate receptor agonist and acts as a key immunomodulator in inflammation. This study aims to investigate the protective influence of FTY720 on inflammation in the DSS-induced colitis model. In the present study, the C57BL/6 mice and the CCR2-/- mice were exposed to 5% Dextran Sodium Sulfate (DSS) drinking water for 6 days followed by an injection of FTY720 (1 mg/kg/d) or vehicle (PBS) 6 times starting on the next day. The body weight, stool consistency, and occult blood were assessed daily. The inflammatory cytokines level in colon tissues and serum were assessed. Leukocyte subsets of bone marrow (BM), spleen, and colon were analyzed by flow cytometry. Our results demonstrated that FTY720 ameliorated the aberrant immune responses by trapping T cells and inhibiting the polarization of M1 macrophages in colitis mice. The effect of FTY720 on the increased number of colonic macrophages did not dependent on CCR2-mediated monocyte influx, despite most monocytes being reduced after DSS administration in the inflamed colon of CCR2-/- mice. Rather, depletion of CCR2 did not impact the protective influence of FTY720 on colonic injury in acute colitis. All these findings unravel a beneficial function of FTY720 in the inflammatory response to DSS-induced acute colitis, provided further insights into monocyte migration and might provide potential opportunities for UC therapeutic intervention.
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Affiliation(s)
- Jing Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Nankai University Affiliated Nankai Hospital, Tianjin, China.
| | - Xin Guan
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Nankai University Affiliated Nankai Hospital, Tianjin, China
| | - Simeng He
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, China
| | - Lixiu Ge
- Department of Clinical Laboratory, Nankai University Affiliated Nankai Hospital, Tianjin, China
| | - Qiaoying Gao
- Department of Clinical Laboratory, Nankai University Affiliated Nankai Hospital, Tianjin, China
| | - Xiaoyang Wu
- Department of Anesthesiology and Critical Care Medicine, Nankai University Affiliated Nankai Hospital, Tianjin, China
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Juneja P, Ruhina Rahman SN, Jakhar D, Mourya AK, Tripathi DM, Kaur I, Tiwari V, Rohilla S, Gupta A, Rawal P, Baweja S, Rastogi A, Naidu V, Sarin SK, Banerjee S, Kaur S. Recombinant VEGF-C (Cys156Ser) improves mesenteric lymphatic drainage and gut immune surveillance in experimental cirrhosis. JHEP Rep 2023; 5:100816. [PMID: 37663117 PMCID: PMC10472308 DOI: 10.1016/j.jhepr.2023.100816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 04/30/2023] [Accepted: 05/24/2023] [Indexed: 09/05/2023] Open
Abstract
Background & Aims Lymphatic vessels (LVs) are crucial for maintaining abdominal fluid homoeostasis and immunity. In cirrhosis, mesenteric LVs (mLVs) are dilated and dysfunctional. Given the established role of vascular endothelial growth factor-C (VEGF-C) in improving LVs, we hypothesised that VEGF-C treatment could ameliorate the functions of mLVs in cirrhosis. Methods In this study, we developed a nanoformulation comprising LV-specific growth factor, recombinant human VEGF-C (Cys156Ser) protein (E-VEGF-C) and delivered it orally in different models of rat cirrhosis to target mLVs. Cirrhotic rats were given nanoformulation without VEGF-C served as vehicles. Drainage of mLVs was analysed using tracer dye. Portal and systemic physiological assessments and computed tomography were performed to measure portal pressures and ascites. Gene expression and permeability of primary mesenteric lymphatic endothelial cells (LyECs) was studied. Immune cells in mesenteric lymph nodes (MLNs) were quantified by flow cytometry. Endogenous and exogenous gut bacterial translocation to MLNs was examined. Results In cirrhotic rats, mLVs were dilated and leaky with impaired drainage. Treatment with E-VEGF-C induced proliferation of mLVs, reduced their diameter, and improved functional drainage. Ascites and portal pressures were significantly reduced in E-VEGF-C rats compared with vehicle rats. In MLNs of E-VEGF-C animals, CD8+CD134+ T cells were increased, whereas CD25+ regulatory T cells were decreased. Both endogenous and exogenous bacterial translocation were limited to MLNs in E-VEGF-C rats with reduced levels of endotoxins in ascites and blood in comparison with those in vehicle rats. E-VEGF-C treatment upregulated the expression of vascular endothelial-cadherin in LyECs and functionally improved the permeability of these cells. Conclusions E-VEGF-C treatment ameliorates mesenteric lymph drainage and portal pressure and strengthens cytotoxic T-cell immunity in MLNs in experimental cirrhosis. It may thus serve as a promising therapy to manage ascites and reduce pathogenic gut bacterial translocation in cirrhosis. Impact and Implications A human recombinant pro-lymphangiogenic growth factor, VEGF-C, was encapsulated in nanolipocarriers (E-VEGF-C) and orally delivered in different models of rat liver cirrhosis to facilitate its gut lymphatic vessel uptake. E-VEGF-C administration significantly increased mesenteric lymphatic vessel proliferation and improved lymph drainage, attenuating abdominal ascites and portal pressures in the animal models. E-VEGF-C treatment limited bacterial translocation to MLNs only with reduced gut bacterial load and ascitic endotoxins. E-VEGF-C therapy thus holds the potential to manage ascites and portal pressure and reduce gut bacterial translocation in patients with cirrhosis.
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Affiliation(s)
- Pinky Juneja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Syed Nazrin Ruhina Rahman
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, India
| | - Deepika Jakhar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akash Kumar Mourya
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dinesh M. Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Impreet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vaibhav Tiwari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sumati Rohilla
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Abhishek Gupta
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Preety Rawal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - V.G.M. Naidu
- Department of Pharmacology and Toxicology, NIPER-Guwahati, Changsari, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Subham Banerjee
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Qi J, Wang J, Zhang Y, Long H, Dong L, Wan P, Zuo Z, Chen W, Song Z. High-Salt-Diet (HSD) aggravates the progression of Inflammatory Bowel Disease (IBD) via regulating epithelial necroptosis. MOLECULAR BIOMEDICINE 2023; 4:28. [PMID: 37691056 PMCID: PMC10493205 DOI: 10.1186/s43556-023-00135-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 06/14/2023] [Indexed: 09/12/2023] Open
Abstract
Due to its unclear etiology, there is no specific medicine to cure the recurrent and incurable inflammatory bowel disease (IBD). Unhealthy dietary habits unconsciously contributed to the progression of IBD, for example a High-Salt-Diet (HSD) is the most neglected and frequently adopted habit. However, the molecular mechanism of how HSD aggravates the progression of IBD has yet to remain uncovered. Herein, we focus on the hypothesis that necroptosis pathway may be involved in the process of IBD exacerbated by HSD. To this end, different gene expression (DEGs) profiles of human epithelia under hypertonic culture conditions were applied to screen candidate pathways. What's more, gene expression manipulation, immune microenvironment detection, RIPK3/MLKL gene knockout (KO), and wild-type (WT) mice were carried out to research the promotion of IBD progression under treatments of high salt intake. Based on our present results, gene expression profiles in human normal colon epithelia cell NCM460 were significantly changed under salt- or sucrose-induced hypertonic culture conditions. RIPK3 was significantly up-regulated under both conditions. Furthermore, mice colon epithelia cell CT26 growth was inhibited in a time- and dose-dependent manner by extra NaCl incubation. Autophagy, and Necroptosis pathways were activated and enhanced by LPS pretreatment. HSD significantly exacerbated DSS-induced IBD symptoms in vivo in a dose-dependent manner. Moreover, RIPK3-/- and MLKL-/- mice presented severe IBD symptoms in vivo. Overall, the results demonstrated that HSD aggravated the IBD progression via necroptosis activation, providing novel strategies and promising targets for the clinical treatment of IBD.
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Affiliation(s)
- Jialong Qi
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
- Yunnan Provincial Key Laboratory of Clinical Virology, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
| | - Jinli Wang
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
| | - Ying Zhang
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
- School of Medicine, Kunming University of Science and Technology, Affiliated By The First People's Hospital of Yunnan Province, Kunming, 650504, Yunnan, P.R. China
| | - Huan Long
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
- School of Medicine, Kunming University of Science and Technology, Affiliated By The First People's Hospital of Yunnan Province, Kunming, 650504, Yunnan, P.R. China
| | - Liang Dong
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
- School of Medicine, Kunming University of Science and Technology, Affiliated By The First People's Hospital of Yunnan Province, Kunming, 650504, Yunnan, P.R. China
| | - Ping Wan
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China
- School of Medicine, Kunming University of Science and Technology, Affiliated By The First People's Hospital of Yunnan Province, Kunming, 650504, Yunnan, P.R. China
| | - Zan Zuo
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China.
| | - Wenjie Chen
- State Key Laboratory of Respiratory Disease, Guangdong-Hongkong-Macao Joint Laboratory of Respiratory Infectious Disease, Guangzhou Medical University, Guangzhou, 510182, P.R. China.
- Sydney Vital Translational Cancer Research Centre, Westbourne St, Sydney, NSW, 2065, Australia.
| | - Zhengji Song
- Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, Kunming, 650032, P.R. China.
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25
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Wang SS, Zhu XX, Wu XY, Zhang WW, Ding YD, Jin SW, Zhang PH. Interaction Between Blood Vasculatures and Lymphatic Vasculatures During Inflammation. J Inflamm Res 2023; 16:3271-3281. [PMID: 37560514 PMCID: PMC10408656 DOI: 10.2147/jir.s414891] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/21/2023] [Indexed: 08/11/2023] Open
Abstract
Physiological activity cannot be regulated without the blood and lymphatic vasculatures, which play complementary roles in maintaining the body's homeostasis and immune responses. Inflammation is the body's initial response to pathological injury and is responsible for protecting the body, removing damaged tissues, and restoring and maintaining homeostasis in the body. A growing number of researches have shown that blood and lymphatic vessels play an essential role in a variety of inflammatory diseases. In the inflammatory state, the permeability of blood vessels and lymphatic vessels is altered, and angiogenesis and lymphangiogenesis subsequently occur. The blood vascular and lymphatic vascular systems interact to determine the development or resolution of inflammation. In this review, we discuss the changes that occur in the blood vascular and lymphatic vascular systems of several organs during inflammation, describe the different scenarios of angiogenesis and lymphangiogenesis at different sites of inflammation, and demonstrate the prospect of targeting the blood vasculature and lymphatic vasculature systems to limit the development of inflammation and promote the resolution of inflammation in inflammatory diseases.
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Affiliation(s)
- Shun-Shun Wang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
| | - Xin-Xu Zhu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
| | - Xin-Yi Wu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
| | - Wen-Wu Zhang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
| | - Yang-Dong Ding
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
| | - Sheng-Wei Jin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
| | - Pu-Hong Zhang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China
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26
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Molon S, Brun P, Scarpa M, Bizzotto D, Zuccolotto G, Scarpa M, Fassan M, Angriman I, Rosato A, Braghetta P, Castagliuolo I, Bonaldo P. Collagen VI promotes recovery from colitis by inducing lymphangiogenesis and drainage of inflammatory cells. J Pathol 2023; 260:417-430. [PMID: 37272555 DOI: 10.1002/path.6092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 04/05/2023] [Accepted: 04/26/2023] [Indexed: 06/06/2023]
Abstract
Despite a number of studies providing evidence that the extracellular matrix (ECM) is an active player in the pathogenesis of intestinal inflammation, knowledge on the actual contribution of specific ECM molecules in the progression of inflammatory bowel disease (IBD) remains scant. Here, we investigated the role of a major ECM protein, collagen VI (ColVI), in gut homeostasis and elucidated the impact of its deregulation on the pathophysiology of IBD. To this end, we combined in vivo and ex vivo studies on wild type and ColVI-deficient (Col6a1-/- ) mice both under physiological conditions and during experimentally induced acute colitis and its subsequent recovery, by means of gut histology and immunostaining, gene expression, bone marrow transplantation, flow cytometry of immune cell subpopulations, and lymph flow assessment. We found that ColVI displayed dynamic expression and ECM deposition during the acute inflammatory and recovery phases of experimentally induced colitis, whereas the genetic ablation of ColVI in Col6a1 null mice impaired the functionality of lymphatic vessels, which in turn affected the resolution of inflammation during colitis. Based on these findings, we investigated ColVI expression and deposition in ileal specimens from two cohorts of patients affected by Crohn's disease (CD) and correlated ColVI abundance to clinical outcome. Our results show that high ColVI immunoreactivity in ileal biopsies of CD patients at diagnosis correlates with increased risk of surgery and that ColVI expression in biopsies taken at the resection margin during surgery, and showing inactive disease, predict disease recurrence. Our data unveil a key role for ColVI in the intestinal microenvironment, where it is involved in lymphangiogenesis and intestinal inflammation. Altogether, these findings point at the dysregulation of ColVI expression as a novel factor contributing to the onset and maintenance of inflammation in CD via mechanisms impinging on the modulation of inflammatory cell recruitment and function. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Sibilla Molon
- Matrix Biology Unit, Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Paola Brun
- Microbiology Unit, Department of Molecular Medicine, University of Padova, Padova, Italy
| | | | - Dario Bizzotto
- Matrix Biology Unit, Department of Molecular Medicine, University of Padova, Padova, Italy
| | | | - Marco Scarpa
- General Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Imerio Angriman
- General Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Antonio Rosato
- Istituto Oncologico Veneto (IOV) - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Paola Braghetta
- Matrix Biology Unit, Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Ignazio Castagliuolo
- Microbiology Unit, Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Paolo Bonaldo
- Matrix Biology Unit, Department of Molecular Medicine, University of Padova, Padova, Italy
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27
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Maisel K, McClain CA, Bogseth A, Thomas SN. Nanotechnologies for Physiology-Informed Drug Delivery to the Lymphatic System. Annu Rev Biomed Eng 2023; 25:233-256. [PMID: 37000965 PMCID: PMC10879987 DOI: 10.1146/annurev-bioeng-092222-034906] [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] [Indexed: 11/05/2023]
Abstract
Accompanying the increasing translational impact of immunotherapeutic strategies to treat and prevent disease has been a broadening interest across both bioscience and bioengineering in the lymphatic system. Herein, the lymphatic system physiology, ranging from its tissue structures to immune functions and effects, is described. Design principles and engineering approaches to analyze and manipulate this tissue system in nanoparticle-based drug delivery applications are also elaborated.
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Affiliation(s)
- Katharina Maisel
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA;
| | - Claire A McClain
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA;
| | - Amanda Bogseth
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA;
| | - Susan N Thomas
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA;
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
- Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Baker ML, Cantley LG. The Lymphatic System in Kidney Disease. KIDNEY360 2023; 4:e841-e850. [PMID: 37019177 PMCID: PMC10371377 DOI: 10.34067/kid.0000000000000120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/07/2023] [Indexed: 04/07/2023]
Abstract
The high-capacity vessels of the lymphatic system drain extravasated fluid and macromolecules from nearly every part of the body. However, far from merely a passive conduit for fluid removal, the lymphatic system also plays a critical and active role in immune surveillance and immune response modulation through the presentation of fluid, macromolecules, and trafficking immune cells to surveillance cells in regional draining lymph nodes before their return to the systemic circulation. The potential effect of this system in numerous disease states both within and outside of the kidney is increasingly being explored for their therapeutic potential. In the kidneys, the lymphatics play a critical role in both fluid and macromolecule removal to maintain oncotic and hydrostatic pressure gradients for normal kidney function, as well as in shaping kidney immunity, and potentially in balancing physiological pathways that promote healthy organ maintenance and responses to injury. In many states of kidney disease, including AKI, the demand on the preexisting lymphatic network increases for clearance of injury-related tissue edema and inflammatory infiltrates. Lymphangiogenesis, stimulated by macrophages, injured resident cells, and other drivers in kidney tissue, is highly prevalent in settings of AKI, CKD, and transplantation. Accumulating evidence points toward lymphangiogenesis being possibly harmful in AKI and kidney allograft rejection, which would potentially position lymphatics as another target for novel therapies to improve outcomes. However, the extent to which lymphangiogenesis is protective rather than maladaptive in the kidney in various settings remains poorly understood and thus an area of active research.
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Affiliation(s)
- Megan L Baker
- Section of Nephrology, Yale School of Medicine, New Haven, Connecticut
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Juneja P, Sharma A, Shasthry SM, Kumar G, Tripathi DM, Rajan V, Rastogi A, Sarin SK, Kaur S. Podoplanin-positive dilated lymphatic vessels in duodenum associates with three-month mortality in patients with cirrhosis. Front Physiol 2023; 14:1045983. [PMID: 37304826 PMCID: PMC10248415 DOI: 10.3389/fphys.2023.1045983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 05/16/2023] [Indexed: 06/13/2023] Open
Abstract
Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.
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Affiliation(s)
- Pinky Juneja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Aarti Sharma
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - S. M. Shasthry
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dinesh M. Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - V. Rajan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Abstract
Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury-induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.
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Affiliation(s)
- Jianyong Zhong
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Annet Kirabo
- Department of Molecular Physiology and Biophysics (A.K.), Vanderbilt University Medical Center, Nashville, TN
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (A.K.)
| | - Hai-Chun Yang
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Agnes B. Fogo
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
- Department of Medicine (A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Elaine L. Shelton
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
| | - Valentina Kon
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
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Song Y, He Y, Rong L, Wang Z, Ma Y, Zhang N, Wang B. "Platelet-coated bullets" biomimetic nanoparticles to ameliorate experimental colitis by targeting endothelial cells. BIOMATERIALS ADVANCES 2023; 148:213378. [PMID: 36963342 DOI: 10.1016/j.bioadv.2023.213378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/28/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023]
Abstract
Intestinal vascular impairment is critical to the recovery of inflammatory bowel disease (IBD), and targeting vascular endothelial cells is a promising emerging therapeutic option. Considering the natural homing properties of platelets to activated vascular endothelium, platelet membrane-mimetic nanoparticles are expected to achieve precise treatment of IBD. Patchouli alcohol (PA) has proven efficacy in experimental colitis, yet its pharmacochemical properties require improvement to enhance efficacy. The rationale for targeting vascular lesions in IBD was analyzed by network pharmacology, and PA-affecting pathways were predicted. PA-encapsulated bio-nanoparticles (PNPs) were constructed to investigate the efficacy of agents on mouse intestinal microvascular endothelial cells (MIMVEC) inflammation model and dextran sulfate sodium (DSS)-induced acute mouse colitis model. PNPs were endocytosed by MIMVEC in vitro and efficiently enriched in inflamed colon. PNPs significantly alleviated the symptoms of experimental colitis and improved neutrophil infiltration. PNPs down-regulated LPS-induced aberrant elevation of il1β, tnfα and il6 mRNAs and reduced p65 phosphorylation in MIMVEC. Intracellular calcium expression, mitochondrial respiration and reactive oxygen species expression were also downregulated by PNPs. PNPs amplified the potency of PA as a calcium antagonist, restrained intracellular Ca2+ perturbations to prevent endothelial activation, which may block leukocyte recruitment in vivo to improve colitis.
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Affiliation(s)
- Yijie Song
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yihao He
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Lan Rong
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Zhicheng Wang
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yueming Ma
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Ning Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Bing Wang
- Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China.
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Promotion of Lymphangiogenesis by Targeted Delivery of VEGF-C Improves Diabetic Wound Healing. Cells 2023; 12:cells12030472. [PMID: 36766814 PMCID: PMC9913977 DOI: 10.3390/cells12030472] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Chronic wounds represent a major therapeutic challenge. Lymphatic vessel function is impaired in chronic ulcers but the role of lymphangiogenesis in wound healing has remained unclear. We found that lymphatic vessels are largely absent from chronic human wounds as evaluated in patient biopsies. Excisional wound healing studies were conducted using transgenic mice with or without an increased number of cutaneous lymphatic vessels, as well as antibody-mediated inhibition of lymphangiogenesis. We found that a lack of lymphatic vessels mediated a proinflammatory wound microenvironment and delayed wound closure, and that the VEGF-C/VEGFR3 signaling axis is required for wound lymphangiogenesis. Treatment of diabetic mice (db/db mice) with the F8-VEGF-C fusion protein that targets the alternatively spliced extra domain A (EDA) of fibronectin, expressed in remodeling tissue, promoted wound healing, and potently induced wound lymphangiogenesis. The treatment also reduced tissue inflammation and exerted beneficial effects on the wound microenvironment, including myofibroblast density and collagen deposition. These findings indicate that activating the lymphatic vasculature might represent a new therapeutic strategy for treating chronic non-healing wounds.
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Cifarelli V, Peche VS, Abumrad NA. Vascular and lymphatic regulation of gastrointestinal function and disease risk. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159207. [PMID: 35882297 PMCID: PMC9642046 DOI: 10.1016/j.bbalip.2022.159207] [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: 01/17/2022] [Revised: 06/17/2022] [Accepted: 07/07/2022] [Indexed: 11/29/2022]
Abstract
The vascular and lymphatic systems in the gut regulate lipid transport while restricting transfer of commensal gut microbiota and directing immune cell trafficking. Increased permeability of the endothelial systems in the intestine associates with passage of antigens and microbiota from the gut into the bloodstream leading to tissue inflammation, the release of pro-inflammatory mediators and ultimately to abnormalities of systemic metabolism. Recent studies show that lipid metabolism maintains homeostasis and function of intestinal blood and lymphatic endothelial cells, BECs and LECs, respectively. This review highlights recent progress in this area, and information related to the contribution of the lipid transporter CD36, abundant in BECs and LECs, to gastrointestinal barrier integrity, inflammation, and to gut regulation of whole body metabolism. The potential role of endothelial lipid delivery in epithelial tissue renewal after injury and consequently in the risk of gastric and intestinal diseases is also discussed.
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Affiliation(s)
- Vincenza Cifarelli
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA.
| | - Vivek S Peche
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
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Abstract
Background Despite great advances in surgical techniques for rotator cuff tear (RCT) over the past decades, the postoperative failure rate of RCT is still high due to the poor healing competence of bone-tendon interface (BTI). The lymphatic vasculature plays a regulatory role in inflammatory disease and affects tissue healing. However, whether lymphangiogenesis and the role of lymphatic vasculature in the physiopathological process of rotator cuff （RC）injury remains unknown. Methods In this study, we constructed a mouse RC injury model and the BTI samples were collected for measurement. Firstly, immunofluorescence was used to investigate the temporal and spatial distribution of lymphangiogenesis in BTI area at different post-injury time points. Subsequently, the mice of experimental group were gavaged with the lymphatic inhibitors (SAR131675) on the first postoperative day to inhibit lymphangiogenesis, while the control group was treated with the vehicle. At postoperative week 2 and 4, the samples were collected for immunofluorescence staining to evaluate lymphatic angiogenesis inhibition. At postoperative week 4 and 8, The supraspinatus (SS) tendon-humeral complexes were collected for bone morphometric, histological and biomechanical tests to assess the healing outcome of the BTI. Results Immunofluorescence results showed that the lymphatic proliferation in the BTI injury area and increased in consistence with the healing time, and the lymphatic hyperplasia area significantly diminished at postoperative week 4. The lymphatic hyperplasia area in the SAR group was significantly lower than that in the control group both at 2 and 4 weeks postoperatively. Moreover, the administration of SAR131675 significantly impeded RC healing, as evidenced by lower histological scores, lower bone morphometric parameters, and worse biomechanical properties in comparison with that in control group at postoperative weeks 4 and 8. Conclusion Lymphangiogenesis plays a positive role in RC healing, and targeting the lymphatic drainage at healing site may be a new therapeutic approach to promote RC injury repair. The translational potential of this article This is the first study to assess the specific role of lymphatic vessels in RC healing, and improving lymphatic drainage may be a potential new therapeutic approach to facilitate repair of BTI. Further, our study provides a reference for possible future treatment of BTI by intervening the lymphatic system.
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Jablonski SA. Pathophysiology, Diagnosis, and Management of Canine Intestinal Lymphangiectasia: A Comparative Review. Animals (Basel) 2022; 12:ani12202791. [PMID: 36290177 PMCID: PMC9597800 DOI: 10.3390/ani12202791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/05/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022] Open
Abstract
Intestinal lymphangiectasia was first described in the dog over 50 years ago. Despite this, canine IL remains poorly understood and challenging to manage. Intestinal lymphangiectasia is characterized by variable intestinal lymphatic dilation, lymphatic obstruction, and/or lymphangitis, and is a common cause of protein-losing enteropathy in the dog. Breed predispositions are suggestive of a genetic cause, but IL can also occur as a secondary process. Similarly, both primary and secondary IL have been described in humans. Intestinal lymphangiectasia is definitively diagnosed via intestinal histopathology, but other diagnostic results can be suggestive of IL. Advanced imaging techniques are frequently utilized to aid in the diagnosis of IL in humans but have not been thoroughly investigated in the dog. Management strategies differ between humans and dogs. Dietary modification is the mainstay of therapy in humans with additional pharmacological therapies occasionally employed, and immunosuppressives are rarely used due to the lack of a recognized immune pathogenesis. In contrast, corticosteroid and immunosuppressive therapies are more commonly utilized in canine IL. This review aims toward a better understanding of canine IL with an emphasis on recent discoveries, comparative aspects, and necessary future investigations.
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Affiliation(s)
- Sara A Jablonski
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
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Zhang L, Ye C, Li P, Li C, Shu W, Zhao Y, Wang X. ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome. Stem Cell Res Ther 2022; 13:448. [PMID: 36064450 PMCID: PMC9442958 DOI: 10.1186/s13287-022-03132-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 08/11/2022] [Indexed: 11/30/2022] Open
Abstract
Background Adipose-derived stem cells (ADSCs) have provided promising applications for Crohn’s disease (CD). However, the practical efficacy of ADSCs remains controversial, and their mechanism is still unclear. Based on the pathogenesis of dysregulated immune responses and abnormal lymphatic alterations in CD, vascular endothelial growth factor-C (VEGF-C) is thought to be a favourable growth factor to optimize ADSCs. We aimed to investigate the efficacy of VEGF-C-stimulated ADSCs and their dual mechanisms in both inhibiting inflammation “IN” and promoting inflammation “OUT” in the intestine. Methods Human stem cells isolated from adipose tissues were identified, pretreated with or without 100 ng/ml VEGF-C and analysed for the secretion of cell culture supernatants in vitro. Lymphatic endothelial cells (LECs) were treated with ADSCs-conditioned medium or co-cultured with ADSCs and VEGF-C stimulated ADSCs. Changes in LECs transmigration, and VEGF-C/VEGFR-3 mRNA levels were assessed by transwell chamber assay and qRT–PCR. ADSCs and VEGF-C-stimulated ADSCs were intraperitoneally injected into mice with TNBS-induced chronic colitis. ADSCs homing and lymphatic vessel density (LVD) were evaluated by immunofluorescence staining. Lymphatic drainage was assessed using Evans blue. Cytokines and growth factors expression was detected respectively by ELISA and qRT–PCR. The protein levels of VEGF-C/VEGFR-3-mediated downstream signals and the NF-κB pathway were assayed by western blot. Faecal microbiota was measured by 16S rRNA sequencing. Results ADSCs stimulated with VEGF-C released higher levels of growth factors (VEGF-C, TGF-β1, and FGF-2) and lower expression of cytokines (IFN-γ and IL-6) in cell supernatants than ADSCs in vitro (all P < 0.05). Secretome released by VEGF-C stimulated ADSCs exhibited a stronger LEC migratory capability and led to elevated VEGF-C/VEGFR-3 expression, but these effects were markedly attenuated by VEGFR-3 inhibitor. VEGF-C-stimulated ADSCs homing to the inflamed colon and mesenteric lymph nodes (MLNs) can exert stronger efficacy in improving colitis symptoms, reducing inflammatory cell infiltration, and significantly enhancing lymphatic drainage. The mRNA levels and protein concentrations of anti-inflammatory cytokines and growth factors were markedly increased with decreased proinflammatory cytokines in the mice treated with VEGF-C-stimulated ADSCs. Systemic administration of VEGF-C-stimulated ADSCs upregulated the colonic VEGF-C/VEGFR-3 pathway and activated downstream AKT and ERK phosphorylation signalling, accompanied by decreased NF-κB p65 expression. A higher abundance of faecal p-Bacteroidetes and lower p-Firmicutes were detected in mice treated with VEGF-C-stimulated ADSCs (all P < 0.05). Conclusion VEGF-C-stimulated ADSCs improve chronic intestinal inflammation by promoting lymphatic drainage and enhancing paracrine signalling via activation of VEGF-C/VEGFR-3-mediated signalling and inhibition of the NF-κB pathway. Our study may provide a new insight into optimizing ADSCs treatment and investigating potential mechanisms in CD. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03132-3.
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Affiliation(s)
- Lei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Chen Ye
- Medical College of Soochow University, Suzhou, 215000, Jiangsu Province, China
| | - Peng Li
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
| | - Chuanding Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Weigang Shu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yujie Zhao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Xiaolei Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Zhang L, Yuan J, Kofi Wiredu Ocansey D, Lu B, Wan A, Chen X, Zhang X, Qiu W, Mao F. Exosomes derived from human umbilical cord mesenchymal stem cells regulate lymphangiogenesis via the miR-302d-3p/VEGFR3/AKT axis to ameliorate inflammatory bowel disease. Int Immunopharmacol 2022; 110:109066. [DOI: 10.1016/j.intimp.2022.109066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/01/2022] [Accepted: 07/12/2022] [Indexed: 11/26/2022]
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Lymphatics act as a signaling hub to regulate intestinal stem cell activity. Cell Stem Cell 2022; 29:1067-1082.e18. [PMID: 35728595 PMCID: PMC9271639 DOI: 10.1016/j.stem.2022.05.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/30/2022] [Accepted: 05/10/2022] [Indexed: 11/22/2022]
Abstract
Barrier epithelia depend upon resident stem cells for homeostasis, defense, and repair. Epithelial stem cells of small and large intestines (ISCs) respond to their local microenvironments (niches) to fulfill a continuous demand for tissue turnover. The complexity of these niches and underlying communication pathways are not fully known. Here, we report a lymphatic network at the intestinal crypt base that intimately associates with ISCs. Employing in vivo loss of function and lymphatic:organoid cocultures, we show that crypt lymphatics maintain ISCs and inhibit their precocious differentiation. Pairing single-cell and spatial transcriptomics, we apply BayesPrism to deconvolve expression within spatial features and develop SpaceFold to robustly map the niche at high resolution, exposing lymphatics as a central signaling hub for the crypt in general and ISCs in particular. We identify WNT-signaling factors (WNT2, R-SPONDIN-3) and a hitherto unappreciated extracellular matrix protein, REELIN, as crypt lymphatic signals that directly govern the regenerative potential of ISCs.
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Jeong J, Tanaka M, Iwakiri Y. Hepatic lymphatic vascular system in health and disease. J Hepatol 2022; 77:206-218. [PMID: 35157960 PMCID: PMC9870070 DOI: 10.1016/j.jhep.2022.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/13/2022] [Accepted: 01/31/2022] [Indexed: 02/07/2023]
Abstract
In recent years, significant advances have been made in the study of lymphatic vessels with the identification of their specific markers and the development of research tools that have accelerated our understanding of their role in tissue homeostasis and disease pathogenesis in many organs. Compared to other organs, the lymphatic system in the liver is understudied despite its obvious importance for hepatic physiology and pathophysiology. In this review, we describe fundamental aspects of the hepatic lymphatic system and its role in a range of liver-related pathological conditions such as portal hypertension, ascites formation, malignant tumours, liver transplantation, congenital liver diseases, non-alcoholic fatty liver disease, and hepatic encephalopathy. The article concludes with a discussion regarding the modulation of lymphangiogenesis as a potential therapeutic strategy for liver diseases.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
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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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Angiogenesis, Lymphangiogenesis, and Inflammation in Chronic Obstructive Pulmonary Disease (COPD): Few Certainties and Many Outstanding Questions. Cells 2022; 11:cells11101720. [PMID: 35626756 PMCID: PMC9139415 DOI: 10.3390/cells11101720] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 02/07/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, predominantly affecting the lung parenchyma and peripheral airways, that results in progressive and irreversible airflow obstruction. COPD development is promoted by persistent pulmonary inflammation in response to several stimuli (e.g., cigarette smoke, bacterial and viral infections, air pollution, etc.). Angiogenesis, the formation of new blood vessels, and lymphangiogenesis, the formation of new lymphatic vessels, are features of airway inflammation in COPD. There is compelling evidence that effector cells of inflammation (lung-resident macrophages and mast cells and infiltrating neutrophils, eosinophils, basophils, lymphocytes, etc.) are major sources of a vast array of angiogenic (e.g., vascular endothelial growth factor-A (VEGF-A), angiopoietins) and/or lymphangiogenic factors (VEGF-C, -D). Further, structural cells, including bronchial and alveolar epithelial cells, endothelial cells, fibroblasts/myofibroblasts, and airway smooth muscle cells, can contribute to inflammation and angiogenesis in COPD. Although there is evidence that alterations of angiogenesis and, to a lesser extent, lymphangiogenesis, are associated with COPD, there are still many unanswered questions.
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Herrada AA, Olate-Briones A, Lazo-Amador R, Liu C, Hernández-Rojas B, Riadi G, Escobedo N. Lymph Leakage Promotes Immunosuppression by Enhancing Anti-Inflammatory Macrophage Polarization. Front Immunol 2022; 13:841641. [PMID: 35663931 PMCID: PMC9160822 DOI: 10.3389/fimmu.2022.841641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
Lymphatic vasculature is a network of capillaries and vessels capable of draining extracellular fluid back to blood circulation and to facilitate immune cell migration. Although the role of the lymphatic vasculature as coordinator of fluid homeostasis has been extensively studied, the consequences of abnormal lymphatic vasculature function and impaired lymph drainage have been mostly unexplored. Here, by using the Prox1+/- mice with defective lymphatic vasculature and lymphatic leakage, we provide evidence showing that lymph leakage induces an immunosuppressive environment by promoting anti-inflammatory M2 macrophage polarization in different inflammatory conditions. In fact, by using a mouse model of tail lymphedema where lymphatic vessels are thermal ablated leading to lymph accumulation, an increasing number of anti-inflammatory M2 macrophages are found in the lymphedematous tissue. Moreover, RNA-seq analysis from different human tumors shows that reduced lymphatic signature, a hallmark of lymphatic dysfunction, is associated with increased M2 and reduced M1 macrophage signatures, impacting the survival of the patients. In summary, we show that lymphatic vascular leakage promotes an immunosuppressive environment by enhancing anti-inflammatory macrophage differentiation, with relevance in clinical conditions such as inflammatory bowel diseases or cancer.
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Affiliation(s)
- Andrés A. Herrada
- Lymphatic Vasculature and Inflammation Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Alexandra Olate-Briones
- Lymphatic Vasculature and Inflammation Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Rodrigo Lazo-Amador
- Lymphatic Vasculature and Inflammation Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Chaohong Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bairon Hernández-Rojas
- Ph.D Program in Sciences Mention in Modeling of Chemical and Biological Systems, Faculty of Engineering, University of Talca, Talca, Chile
| | - Gonzalo Riadi
- Agencia Nacional de Investigación y Desarrollo (ANID) – Millennium Science Initiative Program Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Center for Bioinformatics, Simulation and Modeling, CBSM, Department of Bioinformatics, Faculty of Engineering, University of Talca, Talca, Chile
| | - Noelia Escobedo
- Lymphatic Vasculature and Inflammation Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
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Glinton KE, Ma W, Lantz C, Grigoryeva LS, DeBerge M, Liu X, Febbraio M, Kahn M, Oliver G, Thorp EB. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation. J Clin Invest 2022; 132:e140685. [PMID: 35271504 PMCID: PMC9057589 DOI: 10.1172/jci140685] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 03/08/2022] [Indexed: 11/17/2022] Open
Abstract
Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.
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Affiliation(s)
- Kristofor E. Glinton
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Wanshu Ma
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Connor Lantz
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Lubov S. Grigoryeva
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Matthew DeBerge
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Xiaolei Liu
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Maria Febbraio
- Department of Dentistry and Dental Hygiene, University of Alberta, Edmonton, Alberta, Canada
| | - Mark Kahn
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Guillermo Oliver
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Edward B. Thorp
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- The Heart Center at Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
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Olate-Briones A, Escalona E, Salazar C, Herrada MJ, Liu C, Herrada AA, Escobedo N. The meningeal lymphatic vasculature in neuroinflammation. FASEB J 2022; 36:e22276. [PMID: 35344212 DOI: 10.1096/fj.202101574rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/08/2022] [Accepted: 03/14/2022] [Indexed: 12/13/2022]
Abstract
The lymphatic vasculature is a unidirectional network of lymphatic endothelial cells, whose main role is to maintain fluid homeostasis along with the absorption of dietary fat in the gastrointestinal organs and management and coordination of immune cell trafficking into lymph nodes during homeostasis and under inflammatory conditions. In homeostatic conditions, immune cells, such as dendritic cells, macrophages, or T cells can enter into the lymphatic vasculature and move easily through the lymph reaching secondary lymph nodes where immune cell activation or peripheral tolerance can be modulated. However, under inflammatory conditions such as pathogen infection, increased permeabilization of lymphatic vessels allows faster immune cell migration into inflamed tissues following a chemokine gradient, facilitating pathogen clearance and the resolution of inflammation. Interestingly, since the re-discovery of lymphatic vasculature in the central nervous system, known as the meningeal lymphatic vasculature, the role of these lymphatics as a key player in several neurological disorders has been described, with emphasis on the neurodegenerative process. Alternatively, less has been discussed about meningeal lymphatics and its role in neuroinflammation. In this review, we discuss current knowledge about the anatomy and function of the meningeal lymphatic vasculature and specifically analyze its contribution to different neuroinflammatory processes, highlighting the potential therapeutic target of meningeal lymphatic vasculature in these pathological conditions.
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Affiliation(s)
- Alexandra Olate-Briones
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Emilia Escalona
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Celia Salazar
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | | | - Chaohong Liu
- Department of Microbiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Andrés A Herrada
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Noelia Escobedo
- Lymphatic Vasculature and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
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Masood F, Bhattaram R, Rosenblatt MI, Kazlauskas A, Chang JH, Azar DT. Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression. Front Physiol 2022; 13:846936. [PMID: 35392370 PMCID: PMC8980686 DOI: 10.3389/fphys.2022.846936] [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: 12/31/2021] [Accepted: 02/25/2022] [Indexed: 02/03/2023] Open
Abstract
Aberrant lymphatic system function has been increasingly implicated in pathologies such as lymphedema, organ transplant rejection, cardiovascular disease, obesity, and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. While some pathologies are exacerbated by lymphatic vessel regression and dysfunction, induced lymphatic regression could be therapeutically beneficial in others. Despite its importance, our understanding of lymphatic vessel regression is far behind that of blood vessel regression. Herein, we review the current understanding of blood vessel regression to identify several hallmarks of this phenomenon that can be extended to further our understanding of lymphatic vessel regression. We also summarize current research on lymphatic vessel regression and an array of research tools and models that can be utilized to advance this field. Additionally, we discuss the roles of lymphatic vessel regression and dysfunction in select pathologies, highlighting how an improved understanding of lymphatic vessel regression may yield therapeutic insights for these disease states.
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Yin Y, Zhu ZX, Li Z, Chen YS, Zhu WM. Role of mesenteric component in Crohn’s disease: A friend or foe? World J Gastrointest Surg 2021; 13:1536-1549. [PMID: 35070062 PMCID: PMC8727179 DOI: 10.4240/wjgs.v13.i12.1536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.
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Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen-Xing Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yu-Sheng Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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Solari E, Marcozzi C, Negrini D, Moriondo A. Interplay between Gut Lymphatic Vessels and Microbiota. Cells 2021; 10:cells10102584. [PMID: 34685564 PMCID: PMC8534149 DOI: 10.3390/cells10102584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/20/2021] [Accepted: 09/27/2021] [Indexed: 12/23/2022] Open
Abstract
Lymphatic vessels play a distinctive role in draining fluid, molecules and even cells from interstitial and serosal spaces back to the blood circulation. Lymph vessels of the gut, and especially those located in the villi (called lacteals), not only serve this primary function, but are also responsible for the transport of lipid moieties absorbed by the intestinal mucosa and serve as a second line of defence against possible bacterial infections. Here, we briefly review the current knowledge of the general mechanisms allowing lymph drainage and propulsion and will focus on the most recent findings on the mutual relationship between lacteals and intestinal microbiota.
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Jakovija A, Chtanova T. Neutrophil Interactions with the Lymphatic System. Cells 2021; 10:cells10082106. [PMID: 34440875 PMCID: PMC8393351 DOI: 10.3390/cells10082106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 01/02/2023] Open
Abstract
The lymphatic system is a complex network of lymphatic vessels and lymph nodes designed to balance fluid homeostasis and facilitate host immune defence. Neutrophils are rapidly recruited to sites of inflammation to provide the first line of protection against microbial infections. The traditional view of neutrophils as short-lived cells, whose role is restricted to providing sterilizing immunity at sites of infection, is rapidly evolving to include additional functions at the interface between the innate and adaptive immune systems. Neutrophils travel via the lymphatics from the site of inflammation to transport antigens to lymph nodes. They can also enter lymph nodes from the blood by crossing high endothelial venules. Neutrophil functions in draining lymph nodes include pathogen control and modulation of adaptive immunity. Another facet of neutrophil interactions with the lymphatic system is their ability to promote lymphangiogenesis in draining lymph nodes and inflamed tissues. In this review, we discuss the significance of neutrophil migration to secondary lymphoid organs and within the lymphatic vasculature and highlight emerging evidence of the neutrophils’ role in lymphangiogenesis.
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Affiliation(s)
- Arnolda Jakovija
- Innate and Tumor Immunology Laboratory, Immunity Theme, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
- St Vincent’s School of Medicine, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Tatyana Chtanova
- Innate and Tumor Immunology Laboratory, Immunity Theme, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, NSW 2052, Australia
- Correspondence:
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Geng X, Ho YC, Srinivasan RS. Biochemical and mechanical signals in the lymphatic vasculature. Cell Mol Life Sci 2021; 78:5903-5923. [PMID: 34240226 PMCID: PMC11072415 DOI: 10.1007/s00018-021-03886-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 06/15/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022]
Abstract
Lymphatic vasculature is an integral part of the cardiovascular system where it maintains interstitial fluid balance. Additionally, lymphatic vasculature regulates lipid assimilation and inflammatory response. Lymphatic vasculature is composed of lymphatic capillaries, collecting lymphatic vessels and valves that function in synergy to absorb and transport fluid against gravitational and pressure gradients. Defects in lymphatic vessels or valves leads to fluid accumulation in tissues (lymphedema), chylous ascites, chylothorax, metabolic disorders and inflammation. The past three decades of research has identified numerous molecules that are necessary for the stepwise development of lymphatic vasculature. However, approaches to treat lymphatic disorders are still limited to massages and compression bandages. Hence, better understanding of the mechanisms that regulate lymphatic vascular development and function is urgently needed to develop efficient therapies. Recent research has linked mechanical signals such as shear stress and matrix stiffness with biochemical pathways that regulate lymphatic vessel growth, patterning and maturation and valve formation. The goal of this review article is to highlight these innovative developments and speculate on unanswered questions.
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Affiliation(s)
- Xin Geng
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73013, USA
| | - Yen-Chun Ho
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73013, USA
| | - R Sathish Srinivasan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73013, USA.
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA.
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Ocansey DKW, Pei B, Xu X, Zhang L, Olovo CV, Mao F. Cellular and molecular mediators of lymphangiogenesis in inflammatory bowel disease. J Transl Med 2021; 19:254. [PMID: 34112196 PMCID: PMC8190852 DOI: 10.1186/s12967-021-02922-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
Background Recent studies reporting the intricate crosstalk between cellular and molecular mediators and the lymphatic endothelium in the development of inflammatory bowel diseases (IBD) suggest altered inflammatory cell drainage and lymphatic vasculature, implicating the lymphatic system as a player in the occurrence, development, and recurrence of intestinal diseases. This article aims to review recent data on the modulatory functions of cellular and molecular components of the IBD microenvironment on the lymphatic system, particularly lymphangiogenesis. It serves as a promising therapeutic target for IBD management and treatment. The interaction with gut microbiota is also explored. Main text Evidence shows that cells of the innate and adaptive immune system and certain non-immune cells participate in the complex processes of inflammatory-induced lymphangiogenesis through the secretion of a wide spectrum of molecular factors, which vary greatly among the various cells. Lymphangiogenesis enhances lymphatic fluid drainage, hence reduced infiltration of immunomodulatory cells and associated-inflammatory cytokines. Interestingly, some of the cellular mediators, including mast cells, neutrophils, basophils, monocytes, and lymphatic endothelial cells (LECs), are a source of lymphangiogenic molecules, and a target as they express specific receptors for lymphangiogenic factors. Conclusion The effective target of lymphangiogenesis is expected to provide novel therapeutic interventions for intestinal inflammatory conditions, including IBD, through both immune and non-immune cells and based on cellular and molecular mechanisms of lymphangiogenesis that facilitate inflammation resolution.
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Affiliation(s)
- Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.,Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, 223800, Jiangsu, People's Republic of China
| | - Xinwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Lu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Chinasa Valerie Olovo
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.,Department of Microbiology, University of Nigeria, Nsukka, 410001, Nigeria
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.
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