|
1
|
Salem Y, Yacov N, Kafri P, Propheta-Meiran O, Karni A, Maharshak N, Furer V, Elkayam O, Mendel I. MOSPD2 regulates the activation state of αLβ2 integrin to control monocyte migration: applicability for treatment of chronic inflammatory diseases. Immunol Res 2025; 73:78. [PMID: 40312574 PMCID: PMC12045827 DOI: 10.1007/s12026-025-09633-6] [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: 01/28/2025] [Accepted: 04/21/2025] [Indexed: 05/03/2025]
Abstract
Monocytes are innate immune cells that drive the chronicity of various inflammatory diseases. Monocyte migration to inflamed tissues involves multiple steps of interaction with the vascular endothelium and the extracellular matrix (ECM), a process mediated through conformational transitions in cell surface integrins. We previously described motile sperm domain-containing protein 2 (MOSPD2) as a surface protein expressed on myeloid cells that is essential for the migration of monocytes and a key regulator of inflammation. Investigating MOSPD2's mechanism of action, we assessed whether it plays a role in regulating integrin activation and monocyte adhesion. Data show that silencing of MOSPD2 expression in the THP-1 monocytic cell line significantly increased cell adhesion to various ECM molecules. Employing IW-601, a humanized anti-human MOSDP2 monoclonal antibody, on primary human monocytes increased adhesion to ECM molecules as well as to adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using IW-601 led to a transition in integrin αLβ2 (CD11a/CD18, LFA-1) conformation into an active high-affinity binding form and to the induction of adhesion-associated signaling pathways. Co-immunoprecipitation experiments showed that MOSPD2 binds integrin-β2 (CD18), but not integrin-β1 (CD29). Our results reveal a novel mechanism controlling monocyte migration, in which MOSPD2 acts as an adhesion checkpoint that governs the balance between monocyte adhesion and release. By demonstrating the inhibitory effect of IW-601 on the migration of primary monocytes isolated from patients with chronic inflammatory diseases, we provide proof of concept for translating MOSPD2's mechanism into a potential treatment for inflammatory diseases, further supported by in vivo data in models of RA and IBD.
Collapse
Affiliation(s)
- Yaniv Salem
- ImmuneWalk Therapeutics, SVP Research, 20, Hamagshimim St, 4934829, Petach-Tikva, Israel
- ImmuneWalk Therapeutics, 1 Blue Hill Plaza, Pearl River, NY, 10965, USA
- , Current Address: 77, Shtern Yair St., 5560706, Kiryat-Ono, Israel
| | - Niva Yacov
- ImmuneWalk Therapeutics, SVP Research, 20, Hamagshimim St, 4934829, Petach-Tikva, Israel
- ImmuneWalk Therapeutics, 1 Blue Hill Plaza, Pearl River, NY, 10965, USA
| | - Pinhas Kafri
- ImmuneWalk Therapeutics, SVP Research, 20, Hamagshimim St, 4934829, Petach-Tikva, Israel
- ImmuneWalk Therapeutics, 1 Blue Hill Plaza, Pearl River, NY, 10965, USA
- Current Address: Teva Pharmaceuticals, 12 Hatrufa St, 4250483, Netanya, Israel
| | - Oshrat Propheta-Meiran
- ImmuneWalk Therapeutics, SVP Research, 20, Hamagshimim St, 4934829, Petach-Tikva, Israel
- ImmuneWalk Therapeutics, 1 Blue Hill Plaza, Pearl River, NY, 10965, USA
| | - Arnon Karni
- Neuroimmunology and Multiple Sclerosis Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nitsan Maharshak
- Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Victoria Furer
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ori Elkayam
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Itzhak Mendel
- ImmuneWalk Therapeutics, SVP Research, 20, Hamagshimim St, 4934829, Petach-Tikva, Israel.
- ImmuneWalk Therapeutics, 1 Blue Hill Plaza, Pearl River, NY, 10965, USA.
| |
Collapse
|
|
2
|
Abd El-Gawad EA, Zahran E, Youssuf H, Shehab A, Matter AF. Defatted black soldier fly (Hermetia illucens) diets improved hemato-immunological responses, biochemical parameters, and antioxidant activities in Streptococcus iniae-infected Nile tilapia (Oreochromis niloticus). BMC Vet Res 2025; 21:104. [PMID: 40001064 PMCID: PMC11852831 DOI: 10.1186/s12917-025-04484-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 01/08/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Challenges of limited supply and increasing prices of fishmeal have driven the aquaculture nutritionists to seek alternative sustainable protein rich ingredients to keep manufacturing aquafeeds in a maintainable and cost-effective way. Black soldier fly, Hermetia illucenslarvae meal represent great potential as a sustainable alternative to fishmeal in aquafeeds. METHODS Three replacement diets for fishmeal were prepared at different levels of defatted black soldier fly (Hermetia illucens) meal (DBSFM): Diet 1 (0 g DBSFM /kg diet, control), 33% (DBSFM-33%, 66 g DBSFM /kg diet), and 100% (DBSFM-100%, 200 g DBSFM /kg diet) to investigate their effects on biochemical parameters, immuno-hematological responses, antioxidant activities, and inflammatory gene expression in Nile tilapia, Oreochromis niloticus, a total of 270 (40.0 ± 0.50 g) before and after challenge with Streptococcus iniae (S. iniae). The feeding trial lasted six weeks (pre-challenge) and two weeks (post-challenge). RESULTS The results showed a significant improvement in white blood cell count (P < 0.01), lymphocyte count (P < 0.01), serum lysozyme activity (P < 0.001), and phagocytic activity (P < 0.001), mostly in the DBSFM-100% group following the pre-challenge phase compared to the control group. Post-challenge phase exhibited significant increases in blood indices in the DBSFM-treated groups compared to the control group. Following pre- and post-challenge periods, both DBSFM-supplemented groups experienced significant increases (P < 0.01, P < 0.001), in serum total protein levels. Albumin and globulin levels also experienced similar increases (P < 0.05, P < 0.01), but only post-challenge. Total antioxidant capacity exhibited a significant increase in both DBSFM-supplemented groups following the post-challenge, as did superoxide dismutase, catalase, and glutathione peroxidase in the liver and spleen. Conversely, levels of glucose, cortisol, and malondialdehyde followed the opposite trend. DBSFM-100% inclusion revealed significant (P < 0.05) up-regulation of interleukin 1β (IL-1β) in the pre-challenge phase compared to control, but no significance (P > 0.05) was seen for other genes. Anti-inflammatory-related genes transforming growth factor-β and interleukin-10 mRNA expression levels were up-regulated in DBSFM-supplemented groups compared to the control post-challenge, but the opposite was seen for IL-1β and tumor necrosis factor- α. CONCLUSION These findings suggest that Nile tilapia challenged with S. iniae may experience significant enhancements in hemato-immunological parameters, antioxidant capability, and anti-inflammatory gene expression when fish meal is replaced with DBSFM up to 100%.
Collapse
Affiliation(s)
- Eman A Abd El-Gawad
- Department of Aquatic Animal Medicine, Faculty of Veterinary Medicine, Benha University, Toukh, Kalubia, Egypt.
| | - Eman Zahran
- Department of Aquatic Animal Medicine, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35516, Egypt.
| | - Hadeer Youssuf
- Department of Aquatic Animal Medicine, Faculty of Veterinary Medicine, Benha University, Toukh, Kalubia, Egypt
| | - Ahmed Shehab
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Benha University, Toukh, Kalubia, Egypt
| | - Aya F Matter
- Department of Aquatic Animal Medicine, Faculty of Veterinary Medicine, Benha University, Toukh, Kalubia, Egypt
| |
Collapse
|
|
3
|
Xavier-de-Britto I, Gomes-da-Silva NC, Gomes Soares MA, Follmer C, Dabkiewicz D, Alencar LMR, Sant’Anna C, Ferreira TPT, Martins PRES, Ricci-Junior E, Fechine PBA, Santos-Oliveira R. Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response. ACS Chem Neurosci 2025; 16:699-710. [PMID: 39907698 PMCID: PMC11843614 DOI: 10.1021/acschemneuro.4c00734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/06/2025] Open
Abstract
This study investigates the potential of arimoclomol-loaded nanomicelles for the treatment of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as their anti-inflammatory properties. Arimoclomol, a coinducer of heat shock proteins (HSPs), has shown clinical promise in mitigating protein misfolding, a hallmark of these diseases. In this work, arimoclomol nanomicelles significantly reduced the aggregation of β-amyloid (Aβ1-42) and α-synuclein (α-syn), key pathological proteins in Alzheimer's and Parkinson's. Additionally, the nanomicelles demonstrated potent anti-inflammatory effects, reducing leukocyte and neutrophil counts in an acute inflammation model. These results suggest that arimoclomol nanomicelles could enhance clinical outcomes by targeting both neurodegenerative and inflammatory processes, offering a promising therapeutic strategy for long-term disease management.
Collapse
Affiliation(s)
- Isabelle Xavier-de-Britto
- Brazilian
Nuclear Energy Commission, Nuclear Engineering
Institute, Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Rio de Janeiro, Rio de Janeiro 21941906, Brazil
| | - Natália Cristina Gomes-da-Silva
- Brazilian
Nuclear Energy Commission, Nuclear Engineering
Institute, Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Rio de Janeiro, Rio de Janeiro 21941906, Brazil
| | - Marilia Amável Gomes Soares
- Brazilian
Nuclear Energy Commission, Nuclear Engineering
Institute, Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Rio de Janeiro, Rio de Janeiro 21941906, Brazil
| | - Cristian Follmer
- Laboratory
of Biological Chemistry of Neurodegenerative Disorders, Department
of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
| | - David Dabkiewicz
- Laboratory
of Biological Chemistry of Neurodegenerative Disorders, Department
of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
| | - Luciana Magalhães Rebelo Alencar
- Biophysics
and Nanosystems Laboratory, Federal University of Maranhão, Department of Physics, São Luis, Maranhão 65065690, Brazil
| | - Celso Sant’Anna
- Laboratory
of Microscopy Applied to Life Science–Lamav, National Institute of Metrology, Quality and Technology, Duque de Caxias, Rio de
Janeiro 25250-020, Brazil
| | | | | | - Eduardo Ricci-Junior
- Federal
University of Rio de Janeiro, School of
Pharmacy, Rio de Janeiro, Rio de Janeiro 21941900, Brazil
| | - Pierre Basílio Almeida Fechine
- Group
of Chemistry of Advanced Materials (GQMat)–Department of Analytical
Chemistry and Physical-Chemistry, Federal
University of Ceará, Fortaleza, Ceará 451-970, Brazil
| | - Ralph Santos-Oliveira
- Brazilian
Nuclear Energy Commission, Nuclear Engineering
Institute, Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Rio de Janeiro, Rio de Janeiro 21941906, Brazil
- Rio
de Janeiro State University, Laboratory
of Radiopharmacy and Nanoradiopharmaceuticals, Rio de Janeiro 23070200, Rio de Janeiro, Brazil
| |
Collapse
|
|
4
|
Shubina VS, Kobyakova MI, Penkov NV, Mitenko GV, Udaltsov SN, Shatalin YV. Two Novel Membranes Based on Collagen and Polyphenols for Enhanced Wound Healing. Int J Mol Sci 2024; 25:12353. [PMID: 39596422 PMCID: PMC11594507 DOI: 10.3390/ijms252212353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/12/2024] [Accepted: 11/16/2024] [Indexed: 11/28/2024] Open
Abstract
Two novel membranes based on collagen and two polyphenols, taxifolin pentaglutarate (TfG5) and a conjugate of taxifolin with glyoxylic acid (DfTf), were prepared. Fourier transform infrared spectroscopy examination confirmed the preservation of the triple helical structure of collagen. A scanning electron microscopy study showed that both materials had a porous structure. The incorporation of DfTf into the freeze-dried collagen matrix increased the aggregation of collagen fibers to a higher extent than the incorporation of TfG5, resulting in a more compact structure of the material containing DfTf. It was found that NIH/3T3 mouse fibroblasts were attached to, and relatively evenly spread out on, the surface of both newly obtained membranes. In addition, it was shown that the membranes enhanced skin wound healing in rats with a chemical burn induced by acetic acid. The treatment with the materials led to a faster reepithelization and granulation tissue formation compared with the use of other agents (collagen without polyphenols and buffer saline). It was also found that, in the wound tissue, the level of thiobarbituric acid reactive substances (TBARS) was significantly higher and the level of low-molecular-weight SH-containing compounds (RSH) was significantly lower than those in healthy skin, indicating a rise in oxidative stress at the site of injury. The treatment with collagen membranes containing polyphenols significantly decreased the TBARS level and increased the RSH level, suggesting the antioxidant/anti-inflammatory effect of the materials. The membrane containing TfG5 was more effective than other ones (the collagen membrane containing DfTf and collagen without polyphenols). On the whole, the data obtained indicate that collagen materials containing DfTf and TfG5 have potential as powerful therapeutic agents for the treatment of burn wounds.
Collapse
Affiliation(s)
- Victoria S. Shubina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia;
| | - Margarita I. Kobyakova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia;
| | - Nikita V. Penkov
- Institute of Cell Biophysics, Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institutskaya 3, 142290 Pushchino, Russia;
| | - Gennady V. Mitenko
- Institute of Physicochemical and Biological Problems in Soil Science, Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institutskaya 2, 142290 Pushchino, Russia; (G.V.M.); (S.N.U.)
| | - Sergey N. Udaltsov
- Institute of Physicochemical and Biological Problems in Soil Science, Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institutskaya 2, 142290 Pushchino, Russia; (G.V.M.); (S.N.U.)
| | - Yuri V. Shatalin
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia;
| |
Collapse
|
|
5
|
Mosquera-Sulbaran JA, Pedreañez A, Vargas R, Hernandez-Fonseca JP. Apoptosis in post-streptococcal glomerulonephritis and mechanisms for failed of inflammation resolution. Pediatr Nephrol 2024; 39:1709-1724. [PMID: 37775580 DOI: 10.1007/s00467-023-06162-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 10/01/2023]
Abstract
Post-streptococcal glomerulonephritis is a condition resulting from infection by group A beta-hemolytic streptococcus. The main mechanism involves the formation of immune complexes formed in the circulation or in situ on the glomerular basement membrane, which activates complement and causes various inflammatory processes. Cellular mechanisms have been reported in the induction of kidney damage represented by the infiltration of innate cells (neutrophils and monocyte/macrophages) and adaptive cells (CD4 + lymphocytes and CD8 + lymphocytes) of the immune system. These cells induce kidney damage through various mechanisms. It has been reported that nephritogenic antigens are capable of inducing inflammatory processes early, even before the formation of immune complexes. Usually, this disease progresses towards clinical and renal normalization; however, in a smaller number of patients, it evolves into chronicity and persistent kidney damage. Hypotheses have been proposed regarding the mechanisms underlying this progression to chronicity including failure to induce apoptosis and failure to phagocytose apoptotic cells, allowing these cells to undergo membrane permeabilization and release pro-inflammatory molecules into the environment, thereby perpetuating renal inflammation. Other mechanisms involved include persistent infection, genetic background of the host's complement system, tubulointerstitial changes, and pre-existing kidney damage due to old age and comorbidities.
Collapse
Affiliation(s)
- Jesús A Mosquera-Sulbaran
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette," Facultad de Medicina, Universidad del Zulia, Apartado Postal: 23, Maracaibo, 4001-A, Zulia, Venezuela.
| | - Adriana Pedreañez
- Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Renata Vargas
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette," Facultad de Medicina, Universidad del Zulia, Apartado Postal: 23, Maracaibo, 4001-A, Zulia, Venezuela
| | - Juan Pablo Hernandez-Fonseca
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette," Facultad de Medicina, Universidad del Zulia, Apartado Postal: 23, Maracaibo, 4001-A, Zulia, Venezuela
- Servicio de Microscopia Electrónica del Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
| |
Collapse
|
|
6
|
Hashim N, Babiker R, Mohammed R, Chaitanya NC, Rahman MM, Gismalla B. Highlighting the Effect of Pro-inflammatory Mediators in the Pathogenesis of Periodontal Diseases and Alzheimer's Disease. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2024; 16:S1120-S1128. [PMID: 38882732 PMCID: PMC11174192 DOI: 10.4103/jpbs.jpbs_1120_23] [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: 10/28/2023] [Revised: 11/25/2023] [Accepted: 12/06/2023] [Indexed: 06/18/2024] Open
Abstract
Alzheimer's disease (AD) is a neurological condition that is much more common as people get older. It may start out early or late. Increased levels of pro-inflammatory cytokines and microglial activation, both of which contribute to the central nervous system's inflammatory state, are characteristics of AD. As opposed to this, periodontitis is a widespread oral infection brought on by Gram-negative anaerobic bacteria. By releasing pro-inflammatory cytokines into the systemic circulation, periodontitis can be classified as a "low-grade systemic disease." Periodontitis and AD are linked by inflammation, which is recognized to play a crucial part in both the disease processes. The current review sought to highlight the effects of pro-inflammatory cytokines, which are released during periodontal and Alzheimer's diseases in the pathophysiology of both conditions. It also addresses the puzzling relationship between AD and periodontitis, highlighting the etiology and potential ramifications.
Collapse
Affiliation(s)
- Nada Hashim
- Periodontology, RAK College of Dental Sciences, RAK Medical and Health Sciences University, Ras al-Khaimah, UAE
| | - Rasha Babiker
- Physiology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras al-Khaimah, UAE
| | - Riham Mohammed
- Oral and Maxillofacial Surgery, RAK College of Dental Sciences, RAK Medical and Health Sciences University, Ras al-Khaimah, UAE
| | - Nallan Csk Chaitanya
- Oral Medicine and Radiology, RAK College of Dental Sciences, RAK Medical and Health Sciences University, Ras al-Khaimah, UAE
| | - Muhammed M Rahman
- Periodontology, RAK College of Dental Sciences, RAK Medical and Health Sciences University, Ras al-Khaimah, UAE
| | - Bakri Gismalla
- Periodontology, Faculty of Dentistry, University of Khartoum, Khartoum, Sudan
| |
Collapse
|
|
7
|
Shen CL, Wang R, Santos JM, Elmassry MM, Stephens E, Kim N, Neugebauer V. Ginger alleviates mechanical hypersensitivity and anxio-depressive behavior in rats with diabetic neuropathy through beneficial actions on gut microbiome composition, mitochondria, and neuroimmune cells of colon and spinal cord. Nutr Res 2024; 124:73-84. [PMID: 38402829 PMCID: PMC11466295 DOI: 10.1016/j.nutres.2024.01.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/25/2024] [Accepted: 01/25/2024] [Indexed: 02/27/2024]
Abstract
The relationship among gut microbiota, mitochondrial dysfunction/neuroinflammation, and diabetic neuropathic pain (DNP) has received increased attention. Ginger has antidiabetic and analgesic effects because of its anti-inflammatory property. We examined the effects of gingerols-enriched ginger (GEG) supplementation on pain-associated behaviors, gut microbiome composition, and mitochondrial function and neuroinflammation of colon and spinal cord in DNP rats. Thirty-three male rats were randomly divided into 3 groups: control group, DNP group (high-fat diet plus single dose of streptozotocin at 35 mg/kg body weight, and GEG group (DNP+GEG at 0.75% in the diet for 8 weeks). Von Frey and open field tests were used to assess pain sensitivity and anxio-depressive behaviors, respectively. Colon and spinal cord were collected for gene expression analysis. 16S rRNA gene sequencing was done from cecal samples and microbiome data analysis was performed using QIIME 2. GEG supplementation mitigated mechanical hypersensitivity and anxio-depressive behavior in DNP animals. GEG supplementation suppressed the dynamin-related protein 1 protein expression (colon) and gene expression (spinal cord), astrocytic marker GFAP gene expression (colon and spinal cord), and tumor necrosis factor-α gene expression (colon, P < .05; spinal cord, P = .0974) in DNP rats. GEG supplementation increased microglia/macrophage marker CD11b gene expression in colon and spinal cord of DNP rats. GEG treatment increased abundance of Acinetobacter, Azospirillum, Colidextribacter, and Fournierella but decreased abundance of Muribaculum intestinale in cecal feces of rats. This study demonstrates that GEG supplementation decreased pain, anxio-depression, and neuroimmune cells, and improved the composition of gut microbiomes and mitochondrial function in rats with diabetic neuropathy.
Collapse
Affiliation(s)
- Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX, USA.
| | - Rui Wang
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Julianna Maria Santos
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Moamen M Elmassry
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Emily Stephens
- Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Nicole Kim
- Department of Biology, Texas Tech University, Lubbock, TX, USA
| | - Volker Neugebauer
- Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| |
Collapse
|
|
8
|
Guo Z, Wu Q, Xie P, Wang J, Lv W. Immunomodulation in non-alcoholic fatty liver disease: exploring mechanisms and applications. Front Immunol 2024; 15:1336493. [PMID: 38352880 PMCID: PMC10861763 DOI: 10.3389/fimmu.2024.1336493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) exhibits increased lipid enrichment in hepatocytes. The spectrum of this disease includes stages such as nonalcoholic simple fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and liver fibrosis. Changes in lifestyle behaviors have been a major factor contributing to the increased cases of NAFLD patients globally. Therefore, it is imperative to explore the pathogenesis of NAFLD, identify therapeutic targets, and develop new strategies to improve the clinical management of the disease. Immunoregulation is a strategy through which the organism recognizes and eliminates antigenic foreign bodies to maintain physiological homeostasis. In this process, multiple factors, including immune cells, signaling molecules, and cytokines, play a role in governing the evolution of NAFLD. This review seeks to encapsulate the advancements in research regarding immune regulation in NAFLD, spanning from underlying mechanisms to practical applications.
Collapse
Affiliation(s)
- Ziwei Guo
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qinjuan Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Pengfei Xie
- Guang'anmen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jiuchong Wang
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenliang Lv
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
9
|
Huang S, Chen Y, Gong F, Chen W, Zheng Y, Zhao B, Shi W, Yang Z, Qu H, Mao E, Chen E. Septic macrophages induce T cells immunosuppression in a cell-cell contact manner with the involvement of CR3. Heliyon 2024; 10:e23266. [PMID: 38187232 PMCID: PMC10770445 DOI: 10.1016/j.heliyon.2023.e23266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 11/21/2023] [Accepted: 11/29/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND In addition to excessive inflammation, immunosuppression has been recognized as a contributing factor to poor prognosis of sepsis. Although it has been reported that T cells can become functionally impaired during sepsis, the underlying mechanisms responsible for this phenomenon remain unclear. This study aims to elucidate the mechanisms by which macrophages induce immunosuppression in T cells. METHODS In an in vivo setting, C57BL-6J mice were subjected to cecal ligation and puncture (CLP) with or without depletion of macrophages, and the functions of T cells were assessed. In vitro experiments involved direct co-culture or separate culture of T cells and septic macrophages using a transwell system, followed by analysis of T cell immunity. Additionally, a siRNA targeting CD18 on macrophages was utilized to investigate the role of complement receptor 3 (CR3). RESULTS Both macrophages and T cells exhibited immunosuppression during sepsis. In the in vivo experiments, the absence of macrophages partially alleviated T cell immunosuppression, as evidenced by restored vitality, increased production of TNF-α and IFN-γ, elevated CD8+ T cell levels, and decreased CD25+ T cell levels. In the in vitro experiments, direct co-culture of T cells with septic macrophages resulted in diminished T cell immunity, which was improved when T cells and macrophages were separated by a chamber wall. The expression of CR3 (CD11b/CD18) was upregulated on septic macrophages, and silencing of CD18 led to decreased TNF-α production by T cells, reduced CD4+ T cell numbers, and increased CD25+ T cell numbers. CONCLUSION In sepsis, macrophages induce immunosuppression in T cells through direct cell-cell contact, with the involvement of CR3.
Collapse
Affiliation(s)
- Shunwei Huang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Ying Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Fangchen Gong
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Weiwei Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Yanjun Zheng
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Bing Zhao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Wen Shi
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Zhitao Yang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Hongping Qu
- Department of Intensive Care, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Enqiang Mao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| | - Erzhen Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai, China
| |
Collapse
|
|
10
|
Xiang X, Xin X, Hou Y, Deng Y, Liu X, Yu W. Diosgenin alters LPS-induced macrophage polarization by activating PPARγ/NF-κB signaling pathway. Int Immunopharmacol 2024; 126:111270. [PMID: 38029551 DOI: 10.1016/j.intimp.2023.111270] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023]
Abstract
Diosgenin (DG) is a steroidal saponin derived from plants, and it exhibits anti-inflammatory properties. In this study, we employed an in vitro model of P.g.-LPS-stimulated mouse macrophage cell line RAW264.7 to investigate the anti-inflammatory effects and mechanism of DG under the condition of altered polarization of macrophages. The RAW264.7 cells were subjected to pre-treatment with DG with or without P.g.-LPS. In cultured macrophages, DG inhibited P.g.-LPS-induced pro-inflammatory M1 macrophages, and increased anti-inflammatory M2 macrophages. Notably, DG reduced the expression of phosphorylation levels of NF-κB p65 and IκB while increasing the expression of PPARγ. Further studies revealed that PPARγ inhibitor GW9662 or PPARγ siRNA reversed the inhibitory effect of DG on M1 phenotype. Collectively, the anti-inflammatory mechanism of DG is related to altering macrophage polarization by activating PPARγ and inhibiting NF-κB signaling pathways.
Collapse
Affiliation(s)
- Xingchen Xiang
- Department of Periodontology, Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Xirui Xin
- Department of Periodontology, Hospital of Stomatology, Jilin University, Changchun, China
| | - Yubo Hou
- Department of Periodontology, Hospital of Stomatology, Jilin University, Changchun, China
| | - Yu Deng
- Department of Periodontology, Hospital of Stomatology, Jilin University, Changchun, China
| | - Xinchan Liu
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, China.
| | - Weixian Yu
- Department of Periodontology, Hospital of Stomatology, Jilin University, Changchun, China; Department of Oral Geriatrics, Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China.
| |
Collapse
|
|
11
|
Alvarez-Viejo M, Romero-Rosal L, Perez-Basterrechea M, García-Gala JM, Hernando-Rodriguez P, Marana-Gonzalez J, Rubiera-Valdes M, Vivanco-Allende B, Fernandez-Rodriguez A, Martinez-Revuelta E, Perez-Lopez S. Plasma-Based Scaffold Containing Bone-Marrow Mononuclear Cells Promotes Wound Healing in a Mouse Model of Pressure Injury. Cell Transplant 2024; 33:9636897241251619. [PMID: 38761062 PMCID: PMC11102697 DOI: 10.1177/09636897241251619] [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: 01/12/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 05/20/2024] Open
Abstract
Pressure injuries, or pressure ulcers, are a common problem that may lead to infections and major complications, besides being a social and economic burden due to the costs of treatment and hospitalization. While surgery is sometimes necessary, this also has complications such as recurrence or wound dehiscence. Among the newer methods of pressure injury treatment, advanced therapies are an interesting option. This study examines the healing properties of bone marrow mononuclear cells (BM-MNCs) embedded in a plasma-based scaffold in a mouse model. Pressure ulcers were created on the backs of mice (2 per mouse) using magnets and assigned to a group of ulcers that were left untreated (Control, n = 15), treated with plasma scaffold (Plasma, n = 15), or treated with plasma scaffold containing BM-MNC (Plasma + BM-MNC, n = 15). Each group was examined at three time points (3, 7, and 14 days) after the onset of treatment. At each time point, animals were subjected to biometric assessment, bioluminescence imaging, and tomography. Once treatment had finished, skin biopsies were processed for histological and wound healing reverse transcription polymerase chain reaction (RT-PCR) array studies. While wound closure percentages were higher in the Plasma and Plasma + BM-MNC groups, differences were not significant, and thus descriptive data are provided. In all individuals, the presence of donor cells was revealed by immunohistochemistry on posttreatment onset Days 3, 7, and 14. In the Plasma + BM-MNC group, less inflammation was observed by positron emission tomography-computed tomography (PET/CT) imaging of the mice at 7 days, and a complete morphometabolic response was produced at 14 days, in accordance with histological results. A much more pronounced inflammatory process was observed in controls than in the other two groups, and this persisted until Day 14 after treatment onset. RT-PCR array gene expression patterns were also found to vary significantly, with the greatest difference noted between both treatments at 14 days when 11 genes were differentially expressed.
Collapse
Affiliation(s)
- Maria Alvarez-Viejo
- Unit of Cell Therapy and Regenerative Medicine, Department of Hematology and Hemotherapy, Central University Hospital of Asturias, Oviedo, Spain
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
- University of Oviedo, Oviedo, Spain
| | - Luis Romero-Rosal
- Department of Plastic and Reconstructive Surgery, Central University Hospital of Asturias, Oviedo, Spain
| | - Marcos Perez-Basterrechea
- Unit of Cell Therapy and Regenerative Medicine, Department of Hematology and Hemotherapy, Central University Hospital of Asturias, Oviedo, Spain
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
| | - Jose M. García-Gala
- Unit of Cell Therapy and Regenerative Medicine, Department of Hematology and Hemotherapy, Central University Hospital of Asturias, Oviedo, Spain
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
| | - Pablo Hernando-Rodriguez
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
| | | | - Miriam Rubiera-Valdes
- Pathological Anatomy Service, Central University Hospital of Asturias, Oviedo, Spain
| | | | - Angeles Fernandez-Rodriguez
- Unit of Cell Therapy and Regenerative Medicine, Department of Hematology and Hemotherapy, Central University Hospital of Asturias, Oviedo, Spain
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
| | - Eva Martinez-Revuelta
- Unit of Cell Therapy and Regenerative Medicine, Department of Hematology and Hemotherapy, Central University Hospital of Asturias, Oviedo, Spain
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
| | - Silvia Perez-Lopez
- Unit of Cell Therapy and Regenerative Medicine, Department of Hematology and Hemotherapy, Central University Hospital of Asturias, Oviedo, Spain
- Health Research Institute of the Principality of Asturias-Foundation for Biomedical Research and Innovation in Asturias, Oviedo, Spain
| |
Collapse
|
|
12
|
Etchevers L, Renna MS, Belotti EM, Diaz PU, Salvetti NR, Ortega HH, Amweg AN. ACTH impairs the migratory and secretory profile of mononuclear cells during proestrus in cattle. Res Vet Sci 2023; 164:105031. [PMID: 37804664 DOI: 10.1016/j.rvsc.2023.105031] [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: 06/28/2023] [Revised: 09/21/2023] [Accepted: 09/28/2023] [Indexed: 10/09/2023]
Abstract
The aim was to evaluate the effect of ACTH on the mechanisms involved in peripheral blood mononuclear cells (PBMCs) infiltration into the ovary during dairy cattle proestrus. Regarding this, proper expression pattern of adhesion molecules must take place both in PBMCs and in endothelial cells. Argentinian Holstein cows (n = 12) were treated with 100 IU of ACTH every 12 h for 4 days before ovulation when ovariectomy was performed (day 18). Blood samples were taken on day 15 (0 h) and immediately before (72 h) and after (74 h) the last ACTH administration. In PBMCs, flow cytometry was performed to analyze CD44, CD11b and CD62-L expression along with gene expression of chemokines' receptors. Interleukin (IL)-4 and tumor necrosis factor-α (TNF-α) production was analyzed by flow cytometry after exposing PBMCs to autologous follicular fluid. In ovarian blood vessels, expression of the vascular endothelium cell adhesion-1 (VCAM-1) and the platelet endothelial cell adhesion molecule-1 was evaluated by immunohistochemistry. In T-lymphocytes, the expression of CD44 and CD11b was lower at 72 h in ACTH-treated cows (P < 0.05). In monocytes, the expression of CD11b and CD62-L was lower at 72 h in ACTH-treated cows (P < 0.05). Also, the percentage of IL-4+ cells was higher in ACTH-treated cows, meanwhile, the percentage TNF-α+ cells was lower in ACTH-treated cows (P < 0.05). Finally, in the vessels associated with the preovulatory follicle VCAM-1 immunoexpression was lower in ACTH-treated cows (P < 0.05). Here, we present novel insights into the effect of stress during the preovulatory period on the inflammatory pathway necessary for ovulation.
Collapse
Affiliation(s)
- L Etchevers
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina
| | - M S Renna
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina
| | - E M Belotti
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina
| | - P U Diaz
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina
| | - N R Salvetti
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina
| | - H H Ortega
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina
| | - A N Amweg
- Laboratorio de Biología Celular y Molecular Aplicada, Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) / Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina; Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL), Esperanza, Santa Fe, Argentina.
| |
Collapse
|
|
13
|
Julian JULIAN, Robiatul ADAWIYAH, Sri WAHDINI. BIOMOLECULAR ACTIVITY OF CRYPTOCOCCUS DURING CRYPTOCOCCOSIS: A REVIEW OF MOLECULAR INTERACTIONS OF CRYPTOCOCCUS WITH HUMAN IMMUNE SYSTEM AND BLOOD-BRAIN-BARRIER. Afr J Infect Dis 2023; 18:11-22. [PMID: 38058414 PMCID: PMC10696652 DOI: 10.21010/ajidv18i1.3] [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: 06/08/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 12/08/2023] Open
Abstract
Global mycosis is still a problem. One of these is the cryptococcal disease. A systemic mycosis brought on by Cryptococcus is called cryptococcosis. Host immunological conditions influence infection with Cryptococcosis. When environmental spores are inhaled by the host, the spores get to the lungs, an infection is created. Alveolar macrophages and other immune cells recognize Cryptococcus in the lung. The initial line of defense against pathogens in the phagolysosome is provided by alveolar macrophages found in the lungs. When the immune system is weak, Cryptococcus uses the evasion system as a molecular interaction with the immune system and persists in the lungs without causing any symptoms such as Factor Transcription, Cell masking, N-glycan structure, Extracellular molecule, and Antioxidant system. The evasion mechanism protects and makes Cryptococcus disseminate throughout the other organs, especially CNS. If Cryptococcus escapes against the host immune system, it will disseminate to other organs, especially Cerebrospinal System by Three mechanisms. There are Trojan Horse, Paracellular, and Transcellular interactions with Blood-Brain Barrier. Disease severity is determined by the Interaction between the host's immune system and the fungus.
Collapse
Affiliation(s)
- JULIAN Julian
- Master’s Programme in biomedical science, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - ADAWIYAH Robiatul
- Master’s Programme in biomedical science, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Department of Parasitology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - WAHDINI Sri
- Department of Parasitology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| |
Collapse
|
|
14
|
Lin YC, Tsai WH, Chang SC, Hsu HC. Apoptotic Cell-Derived CD14(+) Microparticles Promote the Phagocytic Activity of Neutrophilic Precursor Cells in the Phagocytosis of Apoptotic Cells. Cells 2023; 12:1983. [PMID: 37566062 PMCID: PMC10417108 DOI: 10.3390/cells12151983] [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: 06/23/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 08/12/2023] Open
Abstract
Membranous CD14 is crucial in the phagocytic activity of neutrophils. However, the role of CD14(+) microparticles (MPs) derived from apoptotic neutrophils (apo-MP) during the phagocytic process is not clear. All trans-retinoic acid (ATRA) induces acute promyelocytic leukemic NB4 cells along granulocytic differentiation. In this study, we investigated the role of CD14(+)apo-MP in the cell-cell interaction during the phagocytic process of apoptotic cells by viable ATRA-NB4 cells. We firstly demonstrate that CD14 expression and phagocytic activity of NB4 cells were upregulated simultaneously after ATRA treatment in a time-dependent manner, and both were significantly enhanced via concurrent lipopolysaccharide treatment. The phagocytic activity of ATRA-NB4 cells and lipopolysaccharide-treated ATRA-NB4 cells were both significantly attenuated by pre-treating cells with an antibody specific to either CD14 or TLR4. Further flow cytometric analysis demonstrates that apoptotic ATRA-NB4 cells release CD14(+)apo-MP in an idarubicin dosage-dependent manner. Both CD14 expression and the phagocytic activity of viable ATRA-NB4 cells were significantly enhanced after incubation with apo-MP harvested from apoptotic ATRA-NB4 cells, and the apo-MP-enhanced phagocytic activity was significantly attenuated by pre-treating apo-MP with an anti-CD14 antibody before incubation with viable cells. We conclude that CD14(+)apo-MP derived from apoptotic ATRA-NB4 cells promotes the phagocytic activity of viable ATRA-NB4 cells in engulfing apoptotic cells.
Collapse
Affiliation(s)
- Yu-Chieh Lin
- Department of Physiology, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan; (Y.-C.L.)
- Sleep Medicine Center, Division of Chest Medicine, Taichung Tzu Chi Hospital, Taichung 427, Taiwan
| | - Wen-Hui Tsai
- Department of Respiratory Therapy, Taipei Medical University, Taipei 106, Taiwan;
| | - Shao-Chi Chang
- Department of Physiology, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan; (Y.-C.L.)
| | - Hui-Chi Hsu
- Department of Medicine, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Division of Hematology & Oncology, Department of Medicine, Cheng-Hsin General Hospital, Taipei 112, Taiwan
| |
Collapse
|
|
15
|
Kirsten N, Ohmes J, Mikkelsen MD, Nguyen TT, Blümel M, Wang F, Tasdemir D, Seekamp A, Meyer AS, Fuchs S. Impact of Enzymatically Extracted High Molecular Weight Fucoidan on Lipopolysaccharide-Induced Endothelial Activation and Leukocyte Adhesion. Mar Drugs 2023; 21:339. [PMID: 37367664 DOI: 10.3390/md21060339] [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: 04/11/2023] [Revised: 05/24/2023] [Accepted: 05/28/2023] [Indexed: 06/28/2023] Open
Abstract
The endothelial cell lining creates an interface between circulating blood and adjoining tissue and forms one of the most critical barriers and targets for therapeutical intervention. Recent studies suggest that fucoidans, sulfated and fucose-rich polysaccharides from brown seaweed, show multiple promising biological effects, including anti-inflammatory properties. However, their biological activity is determined by chemical characteristics such as molecular weight, sulfation degree, and molecular structure, which vary depending on the source, species, and harvesting and isolation method. In this study, we investigated the impact of high molecular weight (HMW) fucoidan extract on endothelial cell activation and interaction with primary monocytes (MNCs) in lipopolysaccharide (LPS)-induced inflammation. Gentle enzyme-assisted extraction combined with fractionation by ion exchange chromatography resulted in well-defined and pure fucoidan fractions. FE_F3, with a molecular weight ranging from 110 to 800 kDa and a sulfate content of 39%, was chosen for further investigation of its anti-inflammatory potential. We observed that along with higher purity of fucoidan fractions, the inflammatory response in endothelial mono- and co-cultures with MNCs was reduced in a dose-dependent manner when testing two different concentrations. This was demonstrated by a decrease in IL-6 and ICAM-1 on gene and protein levels and a reduced gene expression of TLR-4, GSK3β and NF-kB. Expression of selectins and, consequently, the adhesion of monocytes to the endothelial monolayer was reduced after fucoidan treatment. These data indicate that the anti-inflammatory effect of fucoidans increases with their purity and suggest that fucoidans might be useful in limiting the inflammatory response of endothelial cells in cases of LPS-induced bacterial infection.
Collapse
Affiliation(s)
- Nora Kirsten
- Experimental Trauma Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Julia Ohmes
- Experimental Trauma Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Maria Dalgaard Mikkelsen
- Protein Chemistry and Enzyme Technology Section, DTU Bioengineering, Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Thuan Thi Nguyen
- Protein Chemistry and Enzyme Technology Section, DTU Bioengineering, Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Martina Blümel
- GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, 24106 Kiel, Germany
| | - Fanlu Wang
- Experimental Trauma Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Deniz Tasdemir
- GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, 24106 Kiel, Germany
- Faculty of Mathematics and Natural Science, Kiel University, 24118 Kiel, Germany
| | - Andreas Seekamp
- Experimental Trauma Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Anne S Meyer
- Protein Chemistry and Enzyme Technology Section, DTU Bioengineering, Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Sabine Fuchs
- Experimental Trauma Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| |
Collapse
|
|
16
|
Lim HK, Bae S, Han K, Kang BM, Jeong Y, Kim SG, Suh M. Seizure-induced neutrophil adhesion in brain capillaries leads to a decrease in postictal cerebral blood flow. iScience 2023; 26:106655. [PMID: 37168551 PMCID: PMC10164910 DOI: 10.1016/j.isci.2023.106655] [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: 12/18/2022] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 05/13/2023] Open
Abstract
Cerebral hypoperfusion has been proposed as a potential cause of postictal neurological dysfunction in epilepsy, but its underlying mechanism is still unclear. We show that a 30% reduction in postictal cerebral blood flow (CBF) has two contributing factors: the early hypoperfusion up to ∼30 min post-seizure was mainly induced by arteriolar constriction, while the hypoperfusion that persisted for over an hour was due to increased capillary stalling induced by neutrophil adhesion to brain capillaries, decreased red blood cell (RBC) flow accompanied by constriction of capillaries and venules, and elevated intercellular adhesion molecule-1 (ICAM-1) expression. Administration of antibodies against the neutrophil marker Ly6G and against LFA-1, which mediates adhesive interactions with ICAM-1, prevented neutrophil adhesion and recovered the prolonged CBF reductions to control levels. Our findings provide evidence that seizure-induced neutrophil adhesion to cerebral microvessels via ICAM-1 leads to prolonged postictal hypoperfusion, which may underlie neurological dysfunction in epilepsy.
Collapse
Affiliation(s)
- Hyun-Kyoung Lim
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, South Korea
- Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon 16419, South Korea
| | - Sungjun Bae
- Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, South Korea
- IMNEWRUN Inc, N Center Bldg. A 5F, Sungkyunkwan University, Suwon 16419, South Korea
| | - Kayoung Han
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, South Korea
- Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon 16419, South Korea
| | - Bok-Man Kang
- IMNEWRUN Inc, N Center Bldg. A 5F, Sungkyunkwan University, Suwon 16419, South Korea
| | - Yoonyi Jeong
- Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon 16419, South Korea
- Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, South Korea
- Department of Intelligent Precision Healthcare Convergence (IPHC), Sungkyunkwan University, Suwon 16419, South Korea
| | - Seong-Gi Kim
- Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon 16419, South Korea
- Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, South Korea
- Department of Intelligent Precision Healthcare Convergence (IPHC), Sungkyunkwan University, Suwon 16419, South Korea
| | - Minah Suh
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, South Korea
- Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon 16419, South Korea
- Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, South Korea
- IMNEWRUN Inc, N Center Bldg. A 5F, Sungkyunkwan University, Suwon 16419, South Korea
- Department of Intelligent Precision Healthcare Convergence (IPHC), Sungkyunkwan University, Suwon 16419, South Korea
- Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Suwon 16419, South Korea
| |
Collapse
|
|
17
|
Mosaddad SA, Hussain A, Tebyaniyan H. Green Alternatives as Antimicrobial Agents in Mitigating Periodontal Diseases: A Narrative Review. Microorganisms 2023; 11:1269. [PMCID: PMC10220622 DOI: 10.3390/microorganisms11051269] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/26/2023] [Accepted: 05/09/2023] [Indexed: 06/03/2023] Open
Abstract
Periodontal diseases and dental caries are the most common infectious oral diseases impacting oral health globally. Oral cavity health is crucial for enhancing life quality since it serves as the entranceway to general health. The oral microbiome and oral infectious diseases are strongly correlated. Gram-negative anaerobic bacteria have been associated with periodontal diseases. Due to the shortcomings of several antimicrobial medications frequently applied in dentistry, the lack of resources in developing countries, the prevalence of oral inflammatory conditions, and the rise in bacterial antibiotic resistance, there is a need for reliable, efficient, and affordable alternative solutions for the prevention and treatment of periodontal diseases. Several accessible chemical agents can alter the oral microbiota, although these substances also have unfavorable symptoms such as vomiting, diarrhea, and tooth discoloration. Natural phytochemicals generated from plants that have historically been used as medicines are categorized as prospective alternatives due to the ongoing quest for substitute products. This review concentrated on phytochemicals or herbal extracts that impact periodontal diseases by decreasing the formation of dental biofilms and plaques, preventing the proliferation of oral pathogens, and inhibiting bacterial adhesion to surfaces. Investigations examining the effectiveness and safety of plant-based medicines have also been presented, including those conducted over the past decade.
Collapse
Affiliation(s)
- Seyed Ali Mosaddad
- Student Research Committee, School of Dentistry, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran;
| | - Ahmed Hussain
- School of Dentistry, Edmonton Clinic Health Academy, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Hamid Tebyaniyan
- Science and Research Branch, Islimic Azade University, Tehran 14878-92855, Iran
| |
Collapse
|
|
18
|
Ni J, Li G, Dai N, Quan Z, Tong H, Liu Y. Esculin alleviates LPS-induced acute lung injury via inhibiting neutrophil recruitment and migration. Int Immunopharmacol 2023; 119:110177. [PMID: 37068336 PMCID: PMC10105132 DOI: 10.1016/j.intimp.2023.110177] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/25/2023] [Accepted: 04/09/2023] [Indexed: 04/19/2023]
Abstract
OBJECTIVES Acute lung injury (ALI) poses a serious threat to human health globally, particularly with the Coronavirus 2019 (COVID-19) pandemic. Excessive recruitment and infiltration of neutrophils is the major etiopathogenesis of ALI. Esculin, also known as 6,7-dihydroxycoumarin, is a remarkable compound derived from traditional Chinese medicine Cortex fraxini. Accumulated evidence indicates that esculin has potent anti-inflammatory effects, but its pharmaceutical effect against ALI and potential mechanisms are still unclear. METHODS This study evaluated the protective effect of esculin against ALI by histopathological observation and biochemical analysis of lung tissues and bronchoalveolar lavage fluid (BALF) in lipopolysaccharide (LPS)-challenged ALI mice in vivo. The effects of esculin on N-formyl-met-leu-phe (fMLP)-induced neutrophil migration and chemotaxis were quantitatively assessed using a Transwell assay and an automated cell imaging system equipped with a Zigmond chamber, respectively. The drug affinity responsive target stability (DARTS) assay, in vitro protein binding assay and molecular docking were performed to identify the potential therapeutic target of esculin and the potential binding sites and pattern. RESULTS Esculin significantly attenuated LPS-induced lung pathological injury, reduced the levels of pro-inflammatory cytokines in both BALF and lung, and suppressed the activation of NF-κB signaling. Esculin also significantly reduced the number of total cells and neutrophils as well as myeloperoxidase (MPO) activity in the BALF. Esculin impaired neutrophil migration and chemotaxis as evidenced by the reduced migration distance and velocity. Furthermore, esculin remarkably inhibited Vav1 phosphorylation, suppressed Rac1 activation and the PAK1/LIMK1/cofilin signaling axis. Mechanistically, esculin could interact with β2 integrin and then diminish its ligand affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS Esculin inhibits β2 integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.
Collapse
Affiliation(s)
- Jiangwei Ni
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China
| | - Ge Li
- Department of Thoracic Surgery, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, PR China
| | - Ningfeng Dai
- Department of Thoracic Surgery, The Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou 325800, PR China
| | - Zijiao Quan
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, PR China
| | - Haibin Tong
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, PR China.
| | - Yu Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China.
| |
Collapse
|
|
19
|
Consonni FM, Durante B, Manfredi M, Bleve A, Pandolfo C, Garlatti V, Vanella VV, Marengo E, Barberis E, Bottazzi B, Bombace S, My I, Condorelli G, Torri V, Sica A. Immunometabolic interference between cancer and COVID-19. Front Immunol 2023; 14:1168455. [PMID: 37063865 PMCID: PMC10090695 DOI: 10.3389/fimmu.2023.1168455] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/16/2023] [Indexed: 03/31/2023] Open
Abstract
Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNγ mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+-dependent immune homeostasis.
Collapse
Affiliation(s)
- Francesca Maria Consonni
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Barbara Durante
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Marcello Manfredi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Augusto Bleve
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Chiara Pandolfo
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
| | - Valentina Garlatti
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Virginia Vita Vanella
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Emilio Marengo
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
- Department of Sciences and Technological Innovation, University of Piemonte Orientale, Alessandria, Italy
| | - Elettra Barberis
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Barbara Bottazzi
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Sara Bombace
- Department of Cardiovascular Medicine, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Ilaria My
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Gianluigi Condorelli
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
- Department of Cardiovascular Medicine, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Valter Torri
- Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Milan, Italy
| | - Antonio Sica
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
- *Correspondence: Antonio Sica,
| |
Collapse
|
|
20
|
Uriarte SM, Hajishengallis G. Neutrophils in the periodontium: Interactions with pathogens and roles in tissue homeostasis and inflammation. Immunol Rev 2023; 314:93-110. [PMID: 36271881 PMCID: PMC10049968 DOI: 10.1111/imr.13152] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Neutrophils are of key importance in periodontal health and disease. In their absence or when they are functionally defective, as occurs in certain congenital disorders, affected individuals develop severe forms of periodontitis in early age. These observations imply that the presence of immune-competent neutrophils is essential to homeostasis. However, the presence of supernumerary or hyper-responsive neutrophils, either because of systemic priming or innate immune training, leads to imbalanced host-microbe interactions in the periodontium that culminate in dysbiosis and inflammatory tissue breakdown. These disease-provoking imbalanced interactions are further exacerbated by periodontal pathogens capable of subverting neutrophil responses to their microbial community's benefit and the host's detriment. This review attempts a synthesis of these findings for an integrated view of the neutrophils' ambivalent role in periodontal disease and, moreover, discusses how some of these concepts underpin the development of novel therapeutic approaches to treat periodontal disease.
Collapse
Affiliation(s)
- Silvia M. Uriarte
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, USA
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
21
|
Yasmeen N, Selvaraj H, Lakhawat SS, Datta M, Sharma PK, Jain A, Khanna R, Srinivasan J, Kumar V. Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators. Biochem Pharmacol 2023; 209:115437. [PMID: 36731803 PMCID: PMC9884647 DOI: 10.1016/j.bcp.2023.115437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023]
Abstract
Fatal "cytokine storms (CS)" observed in critically ill COVID-19 patients are consequences of dysregulated host immune system and over-exuberant inflammatory response. Acute respiratory distress syndrome (ARDS), multi-system organ failure, and eventual death are distinctive symptoms, attributed to higher morbidity and mortality rates among these patients. Consequent efforts to save critical COVID-19 patients via the usage of several novel therapeutic options are put in force. Strategically, drugs being used in such patients are dexamethasone, remdesivir, hydroxychloroquine, etc. along with the approved vaccines. Moreover, it is certain that activation of the resolution process is important for the prevention of chronic diseases. Until recently Inflammation resolution was considered a passive process, rather it's an active biochemical process that can be achieved by the use of specialized pro-resolving mediators (SPMs). These endogenous mediators are an array of atypical lipid metabolites that include Resolvins, lipoxins, maresins, protectins, considered as immunoresolvents, but their role in COVID-19 is ambiguous. Recent evidence from studies such as the randomized clinical trial, in which omega 3 fatty acid was used as supplement to resolve inflammation in COVID-19, suggests that direct supplementation of SPMs or the use of synthetic SPM mimetics (which are still being explored) could enhance the process of resolution by regulating the aberrant inflammatory process and can be useful in pain relief and tissue remodeling. Here we discussed the biosynthesis of SPMs, & their mechanistic pathways contributing to inflammation resolution along with sequence of events leading to CS in COVID-19, with a focus on therapeutic potential of SPMs.
Collapse
Affiliation(s)
- Nusrath Yasmeen
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Harikrishnan Selvaraj
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Sudarshan S Lakhawat
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Manali Datta
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Pushpender K Sharma
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Ajay Jain
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Rakhi Khanna
- Rajasthan State Regional Forensic Science Laboratory, Kota, Rajasthan, India
| | | | - Vikram Kumar
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India.
| |
Collapse
|
|
22
|
Makievskaya CI, Popkov VA, Andrianova NV, Liao X, Zorov DB, Plotnikov EY. Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential. Int J Mol Sci 2023; 24:2576. [PMID: 36768899 PMCID: PMC9916612 DOI: 10.3390/ijms24032576] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/17/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia-reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.
Collapse
Affiliation(s)
- Ciara I. Makievskaya
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Vasily A. Popkov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Nadezda V. Andrianova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Xinyu Liao
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Dmitry B. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Egor Y. Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| |
Collapse
|
|
23
|
Tvaroška I, Kozmon S, Kóňa J. Molecular Modeling Insights into the Structure and Behavior of Integrins: A Review. Cells 2023; 12:cells12020324. [PMID: 36672259 PMCID: PMC9856412 DOI: 10.3390/cells12020324] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Integrins are heterodimeric glycoproteins crucial to the physiology and pathology of many biological functions. As adhesion molecules, they mediate immune cell trafficking, migration, and immunological synapse formation during inflammation and cancer. The recognition of the vital roles of integrins in various diseases revealed their therapeutic potential. Despite the great effort in the last thirty years, up to now, only seven integrin-based drugs have entered the market. Recent progress in deciphering integrin functions, signaling, and interactions with ligands, along with advancement in rational drug design strategies, provide an opportunity to exploit their therapeutic potential and discover novel agents. This review will discuss the molecular modeling methods used in determining integrins' dynamic properties and in providing information toward understanding their properties and function at the atomic level. Then, we will survey the relevant contributions and the current understanding of integrin structure, activation, the binding of essential ligands, and the role of molecular modeling methods in the rational design of antagonists. We will emphasize the role played by molecular modeling methods in progress in these areas and the designing of integrin antagonists.
Collapse
Affiliation(s)
- Igor Tvaroška
- Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
- Correspondence:
| | - Stanislav Kozmon
- Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
- Medical Vision o. z., Záhradnícka 4837/55, 821 08 Bratislava, Slovakia
| | - Juraj Kóňa
- Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
- Medical Vision o. z., Záhradnícka 4837/55, 821 08 Bratislava, Slovakia
| |
Collapse
|
|
24
|
Wang YH, Tsai CH, Liu SC, Chen HT, Chang JW, Ko CY, Hsu CJ, Chang TK, Tang CH. miR-150-5p and XIST interaction controls monocyte adherence: Implications for osteoarthritis therapy. Front Immunol 2022; 13:1004334. [PMID: 36203618 PMCID: PMC9530358 DOI: 10.3389/fimmu.2022.1004334] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/02/2022] [Indexed: 11/23/2022] Open
Abstract
Recent literature highlights the importance of microRNAs (miRNAs) functioning as diagnostic biomarkers and therapeutic agents in osteoarthritis (OA) and regulators of gene expression. In OA pathogenesis, cell adhesion molecules (CAMs), especially vascular cell adhesion protein 1 (VCAM-1), recruit monocyte infiltration to inflamed synovial tissues and thus accelerate OA progression. Up until now, little has been known about the regulatory mechanisms between miRNAs, long non-coding RNAs (lncRNAs) and VCAM-1 during OA progression. The evidence in this article emphasizes that the functional feature of miR-150-5p is an interaction with the lncRNA X-inactive specific transcript (XIST), which regulates VCAM-1-dependent monocyte adherence in OA synovial fibroblasts (OASFs). Levels of VCAM-1, CD11b (a monocyte marker) and XIST expression were higher in human synovial tissue samples and OASFs, while levels of miR-150-5p were lower in human OA synovial tissue compared with non-OA specimens. XIST enhanced VCAM-1-dependent monocyte adherence to OASFs. Upregulation of miR-150-5p inhibited the effects of XIST upon monocyte adherence. Administration of miR-150-5p effectively ameliorated OA severity in anterior cruciate ligament transection (ACLT) rats. The interaction of miR-150-5p and XIST regulated VCAM-1-dependent monocyte adherence and attenuated OA progression. Our findings suggest that miR-150-5p is a promising small-molecule therapeutic strategy for OA.
Collapse
Affiliation(s)
- Yu-Han Wang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Chun-Hao Tsai
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Shan-Chi Liu
- Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Hsien-Te Chen
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Jun-Way Chang
- The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan
| | - Chih-Yuan Ko
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chin-Jung Hsu
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Ting-Kuo Chang
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
- Division of Spine Surgery, Department of Orthopedic Surgery, MacKay Memorial Hospital, New Taipei, Taiwan
- *Correspondence: Chih-Hsin Tang, ; Ting-Kuo Chang,
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
- *Correspondence: Chih-Hsin Tang, ; Ting-Kuo Chang,
| |
Collapse
|
|
25
|
Jiang B, Ding T, Guo C, Bai X, Cao D, Wu X, Sha W, Jiang M, Wu L, Gao Y. NFAT1 Orchestrates Spinal Microglial Transcription and Promotes Microglial Proliferation via c-MYC Contributing to Nerve Injury-Induced Neuropathic Pain. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201300. [PMID: 35892263 PMCID: PMC9507349 DOI: 10.1002/advs.202201300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/17/2022] [Indexed: 05/17/2023]
Abstract
Peripheral nerve injury-induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T-cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2-mediated DNA demethylation. Global or microglia-specific deletion of Nfat1 attenuates SNL-induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia-related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il-1b, and c-Myc in the spinal cord. Microglia-specific overexpression of c-MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c-MYC by intrathecal injection of inhibitor or siRNA alleviates SNL-induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c-MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.
Collapse
Affiliation(s)
- Bao‐Chun Jiang
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Ting‐Yu Ding
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Chang‐Yun Guo
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Xue‐Hui Bai
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - De‐Li Cao
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Xiao‐Bo Wu
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Wei‐Lin Sha
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Ming Jiang
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| | - Long‐Jun Wu
- Department of NeurologyMayo ClinicRochesterMN55905USA
| | - Yong‐Jing Gao
- Institute of Pain Medicine and Special Environmental MedicineCo‐innovation Center of NeuroregenerationNantong UniversityJiangsu226019China
| |
Collapse
|
|
26
|
Impact of Primary RPE Cells in a Porcine Organotypic Co-Cultivation Model. Biomolecules 2022; 12:biom12070990. [PMID: 35883547 PMCID: PMC9313304 DOI: 10.3390/biom12070990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/04/2022] [Accepted: 07/13/2022] [Indexed: 12/10/2022] Open
Abstract
The pathological events of age-related macular degeneration are characterized by degenerative processes involving the photoreceptor cells, retinal pigment epithelium (RPE), and the Bruch's membrane as well as choroidal alterations. To mimic in vivo interactions between photoreceptor cells and RPE cells ex vivo, complex models are required. Hence, the aim of this study was to establish a porcine organotypic co-cultivation model and enlighten the interactions of photoreceptor and RPE cells, with a special emphasis on potential neuroprotective effects. Porcine neuroretina explants were cultured with primary porcine RPE cells (ppRPE) or medium derived from these cells (=conditioned medium). Neuroretina explants cultured alone served as controls. After eight days, RT-qPCR and immunohistology were performed to analyze photoreceptors, synapses, macroglia, microglia, complement factors, and pro-inflammatory cytokines (e.g., IL1B, IL6, TNF) in the neuroretina samples. The presence of ppRPE cells preserved photoreceptors, whereas synaptical density was unaltered. Interestingly, on an immunohistological as well as on an mRNA level, microglia and complement factors were comparable in all groups. Increased IL6 levels were noted in ppRPE and conditioned medium samples, while TNF was only upregulated in the ppRPE group. IL1B was elevated in conditioned medium samples. In conclusion, a co-cultivation of ppRPE cells and neuroretina seem to have beneficial effects on the neuroretina, preserving photoreceptors and maintaining synaptic vesicles in vitro. This organotypic co-cultivation model can be used to investigate the complex interactions between the retina and RPE cells, gain further insight into neurodegenerative pathomechanisms occurring in retinal diseases, and evaluate potential therapeutics.
Collapse
|
|
27
|
Integrin Regulators in Neutrophils. Cells 2022; 11:cells11132025. [PMID: 35805108 PMCID: PMC9266208 DOI: 10.3390/cells11132025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/17/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
Neutrophils are the most abundant leukocytes in humans and are critical for innate immunity and inflammation. Integrins are critical for neutrophil functions, especially for their recruitment to sites of inflammation or infections. Integrin conformational changes during activation have been heavily investigated but are still not fully understood. Many regulators, such as talin, Rap1-interacting adaptor molecule (RIAM), Rap1, and kindlin, are critical for integrin activation and might be potential targets for integrin-regulating drugs in treating inflammatory diseases. In this review, we outline integrin activation regulators in neutrophils with a focus on the above critical regulators, as well as newly discovered modulators that are involved in integrin activation.
Collapse
|
|
28
|
Kizhakkedathu JN, Conway EM. Biomaterial and cellular implants: foreign surfaces where immunity and coagulation meet. Blood 2022; 139:1987-1998. [PMID: 34415324 DOI: 10.1182/blood.2020007209] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 08/05/2021] [Indexed: 11/20/2022] Open
Abstract
Exposure of blood to a foreign surface in the form of a diagnostic or therapeutic biomaterial device or implanted cells or tissue elicits an immediate, evolutionarily conserved thromboinflammatory response from the host. Primarily designed to protect against invading organisms after an injury, this innate response features instantaneous activation of several blood-borne, highly interactive, well-orchestrated cascades and cellular events that limit bleeding, destroy and eliminate the foreign substance or cells, and promote healing and a return to homeostasis via delicately balanced regenerative processes. In the setting of blood-contacting synthetic or natural biomaterials and implantation of foreign cells or tissues, innate responses are robust, albeit highly context specific. Unfortunately, they tend to be less than adequately regulated by the host's natural anticoagulant or anti-inflammatory pathways, thereby jeopardizing the functional integrity of the device, as well as the health of the host. Strategies to achieve biocompatibility with a sustained return to homeostasis, particularly while the device remains in situ and functional, continue to elude scientists and clinicians. In this review, some of the complex mechanisms by which biomaterials and cellular transplants provide a "hub" for activation and amplification of coagulation and immunity, thromboinflammation, are discussed, with a view toward the development of innovative means of overcoming the innate challenges.
Collapse
Affiliation(s)
- Jayachandran N Kizhakkedathu
- Centre for Blood Research
- Department of Pathology and Laboratory Medicine
- School of Biomedical Engineering, Life Sciences Institute
- Department of Chemistry; and
| | - Edward M Conway
- Centre for Blood Research
- School of Biomedical Engineering, Life Sciences Institute
- Department of Chemistry; and
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
29
|
Yu B, Xue X, Yin Z, Cao L, Li M, Huang J. Engineered Cell Membrane-Derived Nanocarriers: The Enhanced Delivery System for Therapeutic Applications. Front Cell Dev Biol 2022; 10:844050. [PMID: 35295856 PMCID: PMC8918578 DOI: 10.3389/fcell.2022.844050] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/11/2022] [Indexed: 12/15/2022] Open
Abstract
There has been a rapid development of biomimetic platforms using cell membranes as nanocarriers to camouflage nanoparticles for enhancing bio-interfacial capabilities. Various sources of cell membranes have been explored for natural functions such as circulation and targeting effect. Biomedical applications of cell membranes-based delivery systems are expanding from cancer to multiple diseases. However, the natural properties of cell membranes are still far from achieving desired functions and effects as a nanocarrier platform for various diseases. To obtain multi-functionality and multitasking in complex biological systems, various functionalized modifications of cell membranes are being developed based on physical, chemical, and biological methods. Notably, many research opportunities have been initiated at the interface of multi-technologies and cell membranes, opening a promising frontier in therapeutic applications. Herein, the current exploration of natural cell membrane functionality, the design principles for engineered cell membrane-based delivery systems, and the disease applications are reviewed, with a special focus on the emerging strategies in engineering approaches.
Collapse
Affiliation(s)
- Biao Yu
- The Second Affiliated Hospital, Shanghai University, Shanghai, China
- School of Medicine, Shanghai University, Shanghai, China
| | - Xu Xue
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Zhifeng Yin
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai, China
| | - Liehu Cao
- Department of Orthopedics, Luodian Hospital, Shanghai, China
- Department of Orthopedics, Luodian Hospital, Shanghai University, Shanghai, China
| | - Mengmeng Li
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Jianping Huang
- The Second Affiliated Hospital, Shanghai University, Shanghai, China
- Department of Neurology, Wenzhou Central Hospital, Wenzhou, China
| |
Collapse
|
|
30
|
Xia X, Zhang Z, Zhu C, Ni B, Wang S, Yang S, Yu F, Zhao E, Li Q, Zhao G. Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications. Nat Commun 2022; 13:1017. [PMID: 35197446 PMCID: PMC8866499 DOI: 10.1038/s41467-022-28492-5] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/27/2022] [Indexed: 02/07/2023] Open
Abstract
Postoperative abdominal infectious complication (AIC) is associated with metastasis in locally advanced gastric cancer (GC) patients after radical gastrectomy. However, the underlying mechanism remains unclear. Herein, we report that neutrophil extracellular traps (NETs), the DNA meshes released by neutrophils in response to infection, could promote GC cells proliferation, invasion, migration and epithelial-mesenchymal transition dependent on TGF-β signaling. Then we model nude mice with cecal puncture without ligation to simulate postoperative AIC and find that NETs in peripheral blood and ascites fluid facilitate GC cells extravasation and implantation into liver and peritoneum for proliferation and metastasis. Notably, TGF-β signaling inhibitor LY 2157299 could effectively impede liver and peritoneal metastasis but not concurrently aggravate sepsis in those AIC-bearing nude mice. These findings implicate that targeting downstream effectors of NETs such as TGF-β signaling might provide potential therapeutic prospect to reduce the risk of GC metastasis.
Collapse
Affiliation(s)
- Xiang Xia
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Zizhen Zhang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Bo Ni
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Shuchang Wang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Shuofei Yang
- Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Fengrong Yu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Enhao Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
| | - Qing Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200240, Shanghai, People's Republic of China.
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
| |
Collapse
|
|
31
|
Hussen J, Al-Sukruwah MA. The Impact of the Animal Housing System on Immune Cell Composition and Function in the Blood of Dromedary Camels. Animals (Basel) 2022; 12:ani12030317. [PMID: 35158641 PMCID: PMC8833619 DOI: 10.3390/ani12030317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The present study investigated the impacts of a change in animal housing system on selected parameters of the camel immune system. Samples collected from camels during a free-ranging time were compared with samples collected from the same camels during movement-restricted housing. Movement-restricted camels showed elevated myeloperoxidase activity in their serum, a significant shape-change of their neutrophils, and higher reactive oxygen species content in their monocytes and neutrophils. The leukogram pattern of the camels under restricted housing was characterized by increased numbers of neutrophils, eosinophils, lymphocytes, and monocytes. Within the lymphocyte population, only the helper T cells and B cells were expanded in animals under restricted housing. In addition, restricted housing modulated the expression of several cell surface antigens, including monocyte-polarization markers and cell adhesion molecules. Functional analysis of bacterial phagocytosis indicated impaired antibacterial function of phagocytes in camels under restricted housing. In summary, the present study identified significant changes in blood immune cell composition, phenotype, and function in dromedary camels under restricted-housing conditions, and suggests the development of an excitement leukogram in those animals. Abstract Background: The dromedary camel (Camelus dromedarius) is an important livestock animal of desert and semi-desert ecosystems. In recent years, several elements of the camel immune system have been characterized. Stress and excitement induced by animal housing represent the most important environmental factors with potential modulatory effects on the immune system. The present study evaluated the impacts of a restricted-housing system on some phenotypic and functional properties of blood leukocytes in dromedary camels. Methods: Immunofluorescence and flow cytometry were used to comparatively analyze samples collected from camels during a free-ranging time and samples collected from the same camels during movement-restricted housing. Results: In comparison to blood samples collected from the camels during the free-ranging time, samples from movement-restricted camels showed elevated serum myeloperoxidase activity, a significant shape-change in their neutrophils, and higher reactive oxygen species content in their monocytes and neutrophils, indicating increased cellular oxidative stress under movement-restricted housing. The leukogram pattern of the camels under restricted housing was characterized by leukocytosis with increased numbers of neutrophils, eosinophils, lymphocytes, and monocytes, resembling an excitement leukogram pattern. Within the lymphocyte population, only the helper T cells and B cells were expanded in animals under restricted housing. The upregulation of CD163 together with the downregulation of MHC-II on monocytes from excited camels indicate a modulatory potential of animal excitement to polarize monocytes toward an anti-inflammatory phenotype. Functional analysis of bacterial phagocytosis indicates an impaired antibacterial function of phagocytes in excited camels. The downregulation of several cell adhesion molecules on leukocytes from excited camels suggests a role for impaired cell adhesion and tissue migration and leukocyte retention in blood in the observed leukocytosis in animals under excitement. Conclusions: The present study identified significant changes in blood immune cell composition, phenotype, and function in dromedary camels under restricted-housing conditions. The observed changes in leukocyte composition suggest the development of an excitement leukogram pattern in camels under movement-restricted housing. To evaluate the clinical relevance of the observed changes in immune cell phenotype and function for the immune competence of camels under restricted housing, further studies are required.
Collapse
|
|
32
|
Chang CW, Cheng N, Bai Y, Skidgel RA, Du X. Gα 13 Mediates Transendothelial Migration of Neutrophils by Promoting Integrin-Dependent Motility without Affecting Directionality. THE JOURNAL OF IMMUNOLOGY 2021; 207:3038-3049. [PMID: 34799423 DOI: 10.4049/jimmunol.2001385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 10/07/2021] [Indexed: 11/19/2022]
Abstract
Neutrophil migration requires β2 integrins and chemoattractant receptor signaling for motility and directionality. G protein subunit Gα13 can facilitate cell migration by mediating RhoA activation induced by G protein-coupled receptors. However, the possible role of Gα13-integrin interaction in migration is unclear. In this study, we show that Gα13 -/- neutrophils are deficient in transendothelial migration and migration on β2 integrin ligand ICAM-1. However, unlike G protein-coupled receptors and integrin inside-out signaling pathways, Gα13 is important in migration velocity and neutrophil spreading but not in directionality nor cell adhesion. Importantly, neutrophil recruitment in vivo was also inhibited in Gα13 -/- mice, suggesting the importance of Gα13 in transendothelial migration of neutrophils in vitro and in vivo. Furthermore, a synthetic peptide (MB2mP6) derived from the Gα13 binding site of β2 inhibited Gα13-β2 interaction and Gα13-mediated transient RhoA inhibition in neutrophils, suggesting that this peptide inhibited integrin outside-in signaling. MB2mP6 inhibited migration of control neutrophils through endothelial cell monolayers or ICAM-1-coated filters, but was without further effect on Gα13 -/- neutrophils. It also inhibited integrin-dependent neutrophil migration velocity without affecting directionality. In vivo, MB2mP6 markedly inhibited neutrophil infiltration into the cardiac tissues induced by ischemia/reperfusion injury. Thus, Gα13-dependent outside-in signaling enables integrin-dependent neutrophil motility without affecting directionality and may be a new therapeutic target for inhibiting neutrophil trafficking but not adhesion.
Collapse
Affiliation(s)
- Claire W Chang
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.,Department of Bioengineering, University of Illinois at Chicago, Chicago, IL; and
| | - Ni Cheng
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL
| | - Yanyan Bai
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL
| | | | - Xiaoping Du
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
| |
Collapse
|
|
33
|
Tsai WH, Chang SC, Lin YC, Hsu HC. CX3CL1(+) Microparticles-Induced MFG-E8 Enhances Apoptotic Cell Clearance by Alveolar Macrophages. Cells 2021; 10:cells10102583. [PMID: 34685562 PMCID: PMC8533702 DOI: 10.3390/cells10102583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/16/2021] [Accepted: 09/24/2021] [Indexed: 12/20/2022] Open
Abstract
During the resolution phase of acute lung injury, apoptotic cells release CX3CL1 as a “find-me” signal to attract alveolar macrophage transmigration toward apoptotic cells for phagocytosis. However, it is still not clear whether CX3CL1 has pro-phagocytic activity on alveolar macrophage. In this study, we investigated the role of apoptotic NB4 cells-derived CX3CL1(+) microparticles (apo-MP) on the phagocytic activity of NR8383 cells. We demonstrate that exogenous CX3CL1 and apo-MP enhanced the phagocytic activity of NR8383 cells in a CX3 CR1-dependent manner. The apo-MP-enhanced phagocytic activity on NR8383 was attenuated when apo-MP and NR8383 cells were pre-treated with anti-CX3CL1 antibodies and anti-CX3CR1 antibody, respectively, before incubating both for phagocytic assay. Further studies demonstrate that exogenous CX3CL1 and apo-MP also enhanced NR8383 cells in their surface expression and release of MFG-E8 in a CX3CR1 dependent manner. The enhanced phagocytic activity of CX3CL1-treated NR8383 cells was attenuated when NR8383 cells were pre-treated with an anti-MFG-E8 antibody before CX3CL1 treatment. We conclude that apoptotic cell-derived CX3CL1(+) microparticles enhance the phagocytic activity of NR8383 cells by up-regulating their MFG-E8 as a bridge molecule, and these contribute to the formation of phagocytic synapses between apoptotic cells and alveolar macrophages for the subsequent phagocytic clearance of apoptotic cells.
Collapse
Affiliation(s)
- Wen-Hui Tsai
- Department of Respiratory Therapy, Taipei Medical University, Taipei 106, Taiwan;
| | - Shao-Chi Chang
- Department of Physiology, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan; (S.-C.C.); (Y.-C.L.)
| | - Yu-Chieh Lin
- Department of Physiology, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan; (S.-C.C.); (Y.-C.L.)
- Sleep Medicine Center, Division of Chest Medicine, Taichung Tzu Chi Hospital, Taichung 427, Taiwan
| | - Hui-Chi Hsu
- Department of Medicine, School of Medicine, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Division of Hematology & Oncology, Department of Medicine, Chan-Hsin General Hospital, Taipei 112, Taiwan
- Correspondence:
| |
Collapse
|
|
34
|
Nati M, Chung KJ, Chavakis T. The Role of Innate Immune Cells in Nonalcoholic Fatty Liver Disease. J Innate Immun 2021; 14:31-41. [PMID: 34515137 DOI: 10.1159/000518407] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/26/2021] [Indexed: 11/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a very common hepatic pathology featuring steatosis and is linked to obesity and related conditions, such as the metabolic syndrome. When hepatic steatosis is accompanied by inflammation, the disorder is defined as nonalcoholic steatohepatitis (NASH), which in turn can progress toward fibrosis development that can ultimately result in cirrhosis. Cells of innate immunity, such as neutrophils or macrophages, are central regulators of NASH-related inflammation. Recent studies utilizing new experimental technologies, such as single-cell RNA sequencing, have revealed substantial heterogeneity within the macrophage populations of the liver, suggesting distinct functions of liver-resident Kupffer cells and recruited monocyte-derived macrophages with regards to regulation of liver inflammation and progression of NASH pathogenesis. Herein, we discuss recent developments concerning the function of innate immune cell subsets in NAFLD and NASH.
Collapse
Affiliation(s)
- Marina Nati
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.,Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Kyoung-Jin Chung
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.,Paul Langerhans Institute Dresden of Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| |
Collapse
|
|
35
|
Mrugacz M, Bryl A, Falkowski M, Zorena K. Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases. Cells 2021; 10:1703. [PMID: 34359873 PMCID: PMC8305893 DOI: 10.3390/cells10071703] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/02/2021] [Accepted: 07/04/2021] [Indexed: 12/25/2022] Open
Abstract
Integrins belong to a group of cell adhesion molecules (CAMs) which is a large group of membrane-bound proteins. They are responsible for cell attachment to the extracellular matrix (ECM) and signal transduction from the ECM to the cells. Integrins take part in many other biological activities, such as extravasation, cell-to-cell adhesion, migration, cytokine activation and release, and act as receptors for some viruses, including severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). They play a pivotal role in cell proliferation, migration, apoptosis, tissue repair and are involved in the processes that are crucial to infection, inflammation and angiogenesis. Integrins have an important part in normal development and tissue homeostasis, and also in the development of pathological processes in the eye. This review presents the available evidence from human and animal research into integrin structure, classification, function and their role in inflammation, infection and angiogenesis in ocular diseases. Integrin receptors and ligands are clinically interesting and may be promising as new therapeutic targets in the treatment of some eye disorders.
Collapse
Affiliation(s)
- Małgorzata Mrugacz
- Department of Ophthalmology and Eye Rehabilitation, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Anna Bryl
- Department of Ophthalmology and Eye Rehabilitation, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | | | - Katarzyna Zorena
- Department of Immunobiology and Environmental Microbiology, Medical University of Gdansk, 80-211 Gdansk, Poland;
| |
Collapse
|
|
36
|
Stahnke S, Döring H, Kusch C, de Gorter DJJ, Dütting S, Guledani A, Pleines I, Schnoor M, Sixt M, Geffers R, Rohde M, Müsken M, Kage F, Steffen A, Faix J, Nieswandt B, Rottner K, Stradal TEB. Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion. Curr Biol 2021; 31:2051-2064.e8. [PMID: 33711252 DOI: 10.1016/j.cub.2021.02.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 10/12/2020] [Accepted: 02/17/2021] [Indexed: 12/22/2022]
Abstract
Hematopoietic-specific protein 1 (Hem1) is an essential subunit of the WAVE regulatory complex (WRC) in immune cells. WRC is crucial for Arp2/3 complex activation and the protrusion of branched actin filament networks. Moreover, Hem1 loss of function in immune cells causes autoimmune diseases in humans. Here, we show that genetic removal of Hem1 in macrophages diminishes frequency and efficacy of phagocytosis as well as phagocytic cup formation in addition to defects in lamellipodial protrusion and migration. Moreover, Hem1-null macrophages displayed strong defects in cell adhesion despite unaltered podosome formation and concomitant extracellular matrix degradation. Specifically, dynamics of both adhesion and de-adhesion as well as concomitant phosphorylation of paxillin and focal adhesion kinase (FAK) were significantly compromised. Accordingly, disruption of WRC function in non-hematopoietic cells coincided with both defects in adhesion turnover and altered FAK and paxillin phosphorylation. Consistently, platelets exhibited reduced adhesion and diminished integrin αIIbβ3 activation upon WRC removal. Interestingly, adhesion phenotypes, but not lamellipodia formation, were partially rescued by small molecule activation of FAK. A full rescue of the phenotype, including lamellipodia formation, required not only the presence of WRCs but also their binding to and activation by Rac. Collectively, our results uncover that WRC impacts on integrin-dependent processes in a FAK-dependent manner, controlling formation and dismantling of adhesions, relevant for properly grabbing onto extracellular surfaces and particles during cell edge expansion, like in migration or phagocytosis.
Collapse
Affiliation(s)
- Stephanie Stahnke
- Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Hermann Döring
- Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany
| | - Charly Kusch
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - David J J de Gorter
- Institute of Molecular Cell Biology, Westphalian Wilhelms University Münster WWU, Münster, Germany
| | - Sebastian Dütting
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Aleks Guledani
- Institute of Molecular Cell Biology, Westphalian Wilhelms University Münster WWU, Münster, Germany
| | - Irina Pleines
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Michael Schnoor
- Department for Molecular Biomedicine, Centre for Investigation and Advanced Studies of the National Polytechnic Institute (Cinvestav-IPN), 07360 Mexico City, Mexico
| | - Michael Sixt
- Institute of Science and Technology IST Austria, Klosterneuburg, Austria
| | - Robert Geffers
- Genome Analytics Group, Helmholtz Center for Infection Research HZI, Braunschweig, Germany
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Center for Infection Research HZI, Braunschweig, Germany
| | - Mathias Müsken
- Central Facility for Microscopy, Helmholtz Center for Infection Research HZI, Braunschweig, Germany
| | - Frieda Kage
- Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany
| | - Anika Steffen
- Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Jan Faix
- Institute for Biophysical Chemistry, Hannover Medical School MHH, 30625 Hannover, Germany
| | - Bernhard Nieswandt
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Klemens Rottner
- Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany; Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany
| | - Theresia E B Stradal
- Department of Cell Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
| |
Collapse
|
|
37
|
Osaka M, Deushi M, Aoyama J, Funakoshi T, Ishigami A, Yoshida M. High-Fat Diet Enhances Neutrophil Adhesion in LDLR-Null Mice Via Hypercitrullination of Histone H3. ACTA ACUST UNITED AC 2021; 6:507-523. [PMID: 34222722 PMCID: PMC8246031 DOI: 10.1016/j.jacbts.2021.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/21/2022]
Abstract
Neutrophil adhesion on the atheroprone femoral artery of high-fat diet-fed low-density lipoprotein receptor-null mice was enhanced more than in wild-type mice. The inhibition of histone H3 citrullination of neutrophils reversed the enhancement of neutrophil adhesion, suggesting that hypercitrullination contributes to enhanced neutrophil adhesion. Furthermore, pemafibrate reduced the citrullination of histone H3 in these mice. Therefore, the hypercitrullination of histone H3 in neutrophils contributes to atherosclerotic vascular inflammation.
Collapse
Key Words
- BM, bone marrow
- BW, body weight
- DNaseI, deoxyribonuclease I
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- HFD, high-fat diet
- HUVECs, human umbilical vein endothelial cells
- IVM, intravital microscopy
- LDLR, low-density lipoprotein receptor
- LysM, lysosome M
- MPO, myeloperoxidase
- NC, normal chow
- NE, neutrophil elastase
- NET, neutrophil extracellular trap
- PAD4, peptidylarginine deiminase 4
- PPAR, peroxisome proliferator-activated receptor
- TC, total cholesterol
- TDFA, N-acetyl-l-threonyl-l-α-aspartyl-N5-(2-fluoro-1-iminoethyl)-l-ornithinamide trifluoroacetate salt
- TG, triglyceride
- citrullination
- cxcl1
- eGFP, enhanced green fluorescent protein
- in vivo imaging
- neutrophil
- vascular inflammation
- wt, wild type
Collapse
Affiliation(s)
- Mizuko Osaka
- Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Nutrition and Metabolism in Cardiovascular Disease, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Michiyo Deushi
- Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jiro Aoyama
- Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomoko Funakoshi
- Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.,Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akihito Ishigami
- Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Masayuki Yoshida
- Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| |
Collapse
|
|
38
|
Zidar A, Kristl J, Kocbek P, Zupančič Š. Treatment challenges and delivery systems in immunomodulation and probiotic therapies for periodontitis. Expert Opin Drug Deliv 2021; 18:1229-1244. [PMID: 33760648 DOI: 10.1080/17425247.2021.1908260] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Periodontitis is a widespread illness that arises due to disrupted interplay between the oral microbiota and the host immune response. In some cases, conventional therapies can provide temporary remission, although this is often followed by disease relapse. Recent studies of periodontitis pathology have promoted the development of new therapeutics to improve treatment options, together with local application using advanced drug delivery systems.Areas covered: This paper provides a critical review of the status of current treatment approaches to periodontitis, with a focus on promising immunomodulation and probiotic therapies. These are based on delivery of small molecules, peptides, proteins, DNA or RNA, and probiotics. The key findings on novel treatment strategies and formulation of advanced delivery systems, such as nanoparticles and nanofibers, are highlighted.Expert opinion: Multitarget therapy based on antimicrobial, immunomodulatory, and probiotic active ingredients incorporated into advanced delivery systems for application to the periodontal pocket can improve periodontitis treatment outcomes. Translation of such adjuvant therapy from laboratory to patient is expected in the future.
Collapse
Affiliation(s)
- Anže Zidar
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Julijana Kristl
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Petra Kocbek
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Špela Zupančič
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| |
Collapse
|
|
39
|
Martin S, Maus S, Stemler T, Rosar F, Khreish F, Holland JP, Ezziddin S, Bartholomä MD. Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of 64Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates. Mol Imaging Biol 2021; 23:95-108. [PMID: 32856224 PMCID: PMC7782405 DOI: 10.1007/s11307-020-01530-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/14/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three five-membered azaheterocyclic arms for the preparation of 68Ga- and 64Cu-based radiopharmaceuticals. Based on this platform, the chelator scaffold NOTI-TVA with three additional carboxylic acid groups for bioconjugation was synthesized and characterized. The primary aims of this proof-of-concept study were (1) to evaluate if trimeric radiotracers on the basis of the NOTI-TVA 6 scaffold can be developed, (2) to determine if the additional substituents for bioconjugation at the non-coordinating NH atoms of the imidazole residues of the building block NOTI influence the metal binding properties, and (3) what influence multiple targeting vectors have on the biological performance of the radiotracer. The cyclic RGDfK peptide that specifically binds to the αvß3 integrin receptor was selected as the biological model system. PROCEDURES Two different synthetic routes for the preparation of NOTI-TVA 6 were explored. Three c(RGDfK) peptide residues were conjugated to the NOTI-TVA 6 building block by standard peptide chemistry providing the trimeric bioconjugate NOTI-TVA-c(RGDfK)3 9. Labeling of 9 with [64Cu]CuCl2 was performed manually at pH 8.2 at ambient temperature. Binding affinities of Cu-8, the Cu2+ complex of the previously described monomer NODIA-Me-c(RGDfK) 8, and the trimer Cu-9 to integrin αvß3 were determined in competitive cell binding experiments in the U-87MG cell line. The pharmacokinetics of both 64Cu-labeled conjugates [64Cu]Cu-8 and [64Cu]Cu-9 were determined by small-animal PET imaging and ex vivo biodistribution studies in mice bearing U-87MG xenografts. RESULTS Depending on the synthetic route, NOTI-TVA 6 was obtained with an overall yield up to 58 %. The bioconjugate 9 was prepared in 41 % yield. Both conjugates [64Cu]Cu-8 and [64Cu]Cu-9 were radiolabeled quantitatively at ambient temperature in high molar activities of Am ~ 20 MBq nmol-1 in less than 5 min. Competitive inhibitory constants IC50 of c(RDGfK) 7, Cu-8, and Cu-9 were determined to be 159.5 ± 1.3 nM, 256.1 ± 2.1 nM, and 99.5 ± 1.1 nM, respectively. In small-animal experiments, both radiotracers specifically delineated αvß3 integrin-positive U-87MG tumors with low uptake in non-target organs and rapid blood clearance. The trimer [64Cu]Cu-9 showed a ~ 2.5-fold higher tumor uptake compared with the monomer [64Cu]Cu-8. CONCLUSIONS Functionalization of NOTI at the non-coordinating NH atoms of the imidazole residues for bioconjugation was straightforward and allowed the preparation of a homotrimeric RGD conjugate. After optimization of the synthesis, required building blocks to make NOTI-TVA 6 are now available on multi-gram scale. Modifications at the imidazole groups had no measurable impact on metal binding properties in vitro and in vivo suggesting that the NOTI scaffold is a promising candidate for the development of 64Cu-labeled multimeric/multifunctional radiotracers.
Collapse
Affiliation(s)
- Sebastian Martin
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Rue de Bugnon 25A, CH-1011, Lausanne, Switzerland
| | - Stephan Maus
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Tobias Stemler
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Florian Rosar
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Fadi Khreish
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Jason P Holland
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Samer Ezziddin
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany
| | - Mark D Bartholomä
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, D-66421, Homburg, Germany.
- Department of Nuclear Medicine, University of Freiburg - Medical Center, Hugstetterstrasse 55, 79106, Freiburg, Germany.
| |
Collapse
|
|
40
|
Directional mast cell degranulation of tumor necrosis factor into blood vessels primes neutrophil extravasation. Immunity 2021; 54:468-483.e5. [PMID: 33484643 DOI: 10.1016/j.immuni.2020.12.017] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 11/10/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022]
Abstract
Tissue resident mast cells (MCs) rapidly initiate neutrophil infiltration upon inflammatory insult, yet the molecular mechanism is still unknown. Here, we demonstrated that MC-derived tumor necrosis factor (TNF) was crucial for neutrophil extravasation to sites of contact hypersensitivity-induced skin inflammation by promoting intraluminal crawling. MC-derived TNF directly primed circulating neutrophils via TNF receptor-1 (TNFR1) while being dispensable for endothelial cell activation. The MC-derived TNF was infused into the bloodstream by directional degranulation of perivascular MCs that were part of the vascular unit with access to the vessel lumen. Consistently, intravenous administration of MC granules boosted neutrophil extravasation. Pronounced and rapid intravascular MC degranulation was also observed upon IgE crosslinking or LPs challenge indicating a universal MC potential. Consequently, the directional MC degranulation of pro-inflammatory mediators into the bloodstream may represent an important target for therapeutic approaches aimed at dampening cytokine storm syndromes or shock symptoms, or intentionally pushing immune defense.
Collapse
|
|
41
|
Singh R, Sharma P, Wadhwan V. Neutrophils defending the defenders. J Oral Maxillofac Pathol 2021; 25:177-182. [PMID: 34349432 PMCID: PMC8272482 DOI: 10.4103/jomfp.jomfp_495_20] [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: 12/04/2020] [Revised: 02/06/2021] [Accepted: 03/03/2021] [Indexed: 11/29/2022] Open
Abstract
Neutrophils are the most abundant granulocytes which are involved in defense mechanism. As innate immune cells, they are first-line defenders and can perform different functions in the human body to maintain equilibrium. Neutrophils are the main leukocyte and their role in healthy oral cavity is to face pathological changes within oral environment. With regard to these, it has been observed that neutrophils are highly heterogeneous in their behavior. The aim of this review is to give an overview of the role of neutrophils in context of various physiological and pathological conditions.
Collapse
Affiliation(s)
- Roli Singh
- Department of Oral and Maxillofacial Pathology and Oral Microbiology, Subharti Dental College, Meerut, Uttar Pradesh, India
| | - Preeti Sharma
- Department of Oral and Maxillofacial Pathology and Oral Microbiology, Subharti Dental College, Meerut, Uttar Pradesh, India
| | - Vijay Wadhwan
- Department of Oral and Maxillofacial Pathology and Oral Microbiology, Subharti Dental College, Meerut, Uttar Pradesh, India
| |
Collapse
|
|
42
|
Preissner KT, Fischer S, Deindl E. Extracellular RNA as a Versatile DAMP and Alarm Signal That Influences Leukocyte Recruitment in Inflammation and Infection. Front Cell Dev Biol 2020; 8:619221. [PMID: 33392206 PMCID: PMC7775424 DOI: 10.3389/fcell.2020.619221] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022] Open
Abstract
Upon vascular injury, tissue damage, ischemia, or microbial infection, intracellular material such as nucleic acids and histones is liberated and comes into contact with the vessel wall and circulating blood cells. Such "Danger-associated molecular patterns" (DAMPs) may thus have an enduring influence on the inflammatory defense process that involves leukocyte recruitment and wound healing reactions. While different species of extracellular RNA (exRNA), including microRNAs and long non-coding RNAs, have been implicated to influence inflammatory processes at different levels, recent in vitro and in vivo work has demonstrated a major impact of ribosomal exRNA as a prominent DAMP on various steps of leukocyte recruitment within the innate immune response. This includes the induction of vascular hyper-permeability and vasogenic edema by exRNA via the activation of the "vascular endothelial growth factor" (VEGF) receptor-2 system, as well as the recruitment of leukocytes to the inflamed endothelium, the M1-type polarization of inflammatory macrophages, or the role of exRNA as a pro-thrombotic cofactor to promote thrombosis. Beyond sterile inflammation, exRNA also augments the docking of bacteria to host cells and the subsequent microbial invasion. Moreover, upon vessel occlusion and ischemia, the shear stress-induced release of exRNA initiates arteriogenesis (i.e., formation of natural vessel bypasses) in a multistep process that resembles leukocyte recruitment. Although exRNA can be counteracted for by natural circulating RNase1, under the conditions mentioned, only the administration of exogenous, thermostable, non-toxic RNase1 provides an effective and safe therapeutic regimen for treating the damaging activities of exRNA. It remains to be investigated whether exRNA may also influence viral infections (including COVID-19), e.g., by supporting the interaction of host cells with viral particles and their subsequent invasion. In fact, as a consequence of the viral infection cycle, massive amounts of exRNA are liberated, which can provoke further tissue damage and enhance virus dissemination. Whether the application of RNase1 in this scenario may help to limit the extent of viral infections like COVID-19 and impact on leukocyte recruitment and emigration steps in immune defense in order to limit the extent of associated cardiovascular diseases remains to be studied.
Collapse
Affiliation(s)
- Klaus T. Preissner
- Department of Biochemistry, Medical School, Justus Liebig University Giessen, Giessen, Germany
- Kerckhoff-Heart-Research-Institute, Department of Cardiology, Medical School, Justus Liebig University Giessen, Giessen, Germany
| | - Silvia Fischer
- Department of Biochemistry, Medical School, Justus Liebig University Giessen, Giessen, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany
| |
Collapse
|
|
43
|
Kalafati L, Mitroulis I, Verginis P, Chavakis T, Kourtzelis I. Neutrophils as Orchestrators in Tumor Development and Metastasis Formation. Front Oncol 2020; 10:581457. [PMID: 33363012 PMCID: PMC7758500 DOI: 10.3389/fonc.2020.581457] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/10/2020] [Indexed: 12/16/2022] Open
Abstract
Several lines of clinical and experimental evidence suggest that immune cell plasticity is a central player in tumorigenesis, tumor progression, and metastasis formation. Neutrophils are able to promote or inhibit tumor growth. Through their interaction with tumor cells or their crosstalk with other immune cell subsets in the tumor microenvironment, they modulate tumor cell survival. Here, we summarize current knowledge with regards to the mechanisms that underlie neutrophil–mediated effects on tumor establishment and metastasis development. We also discuss the tumor-mediated effects on granulopoiesis and neutrophil precursors in the bone marrow and the involvement of neutrophils in anti-tumor therapeutic modalities.
Collapse
Affiliation(s)
- Lydia Kalafati
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Partner Site Dresden and German Cancer Research Center, Heidelberg, Germany
| | - Ioannis Mitroulis
- National Center for Tumor Diseases, Partner Site Dresden and German Cancer Research Center, Heidelberg, Germany.,Department of Hematology and Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Panayotis Verginis
- University of Crete, School of Medicine, Heraklion, Greece.,Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Ioannis Kourtzelis
- York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom
| |
Collapse
|
|
44
|
Strudwick XL, Adams DH, Pyne NT, Samuel MS, Murray RZ, Cowin AJ. Systemic Delivery of Anti-Integrin αL Antibodies Reduces Early Macrophage Recruitment, Inflammation, and Scar Formation in Murine Burn Wounds. Adv Wound Care (New Rochelle) 2020; 9:637-648. [PMID: 33124967 PMCID: PMC7698651 DOI: 10.1089/wound.2019.1035] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 11/17/2019] [Indexed: 12/30/2022] Open
Abstract
Objective: Increased macrophage recruitment in the early stages of wound healing leads to an excessive inflammatory response associated with elevated fibrosis and scarring. This recruitment relies upon integrins on the surface of monocytes that regulate their migration and extravasation from the circulation into the wound site, where they differentiate into macrophages. The aim of this study was to determine if inhibiting monocyte extravasation from the circulation into burns would reduce macrophages numbers in burns and lead to reduced inflammation and scar formation. Approach: Scald burns were created on mice and treated with integrin alpha L (αL) function blocking antibody via intravenous delivery day 1 after injury. The effect of inhibiting macrophage recruitment into the burn was assessed using macro- and microscopic wound parameters as well as immunohistochemistry for inflammatory cell markers, cytokines, and collagen deposition. Results: Burn wound-associated macrophages were reduced by 54.7% at day 3 following treatment with integrin αL antibody, with levels returning to normal by day 7. This reduction in macrophages led to a concomitant reduction in inflammatory mediators, including tumor necrosis factor-alpha (TNFα) and Il-10 as well as a reduction in proscarring transforming growth factor beta 1 (TGFβ1). This reduced inflammatory response was also associated with less alpha smooth muscle actin (αSMA) expression and an overall trend toward reduced scar formation with a lower collagen I/III ratio. Innovation: Treatment of burns with integrin αL function blocking antibodies reduces inflammation in burn wounds. Conclusion: These results suggest that reducing macrophage infiltration into burn wounds may lead to a reduced early inflammatory response and less scar formation following burn injury.
Collapse
Affiliation(s)
- Xanthe L. Strudwick
- Future Industries Institute, University of South Australia, Adelaide, South Australia, Australia
| | - Damian H. Adams
- Future Industries Institute, University of South Australia, Adelaide, South Australia, Australia
| | - Natasha T. Pyne
- Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia
| | - Michael S. Samuel
- Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia
- Faculty of Health and Medical Sciences, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Rachael Z. Murray
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Allison J. Cowin
- Future Industries Institute, University of South Australia, Adelaide, South Australia, Australia
| |
Collapse
|
|
45
|
Martinez L, Li X, Ramos-Echazabal G, Faridi H, Zigmond ZM, Santos Falcon N, Hernandez DR, Shehadeh SA, Velazquez OC, Gupta V, Vazquez-Padron RI. A Genetic Model of Constitutively Active Integrin CD11b/CD18. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:2545-2553. [PMID: 32938725 PMCID: PMC7577938 DOI: 10.4049/jimmunol.1901402] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 08/23/2020] [Indexed: 01/31/2023]
Abstract
Pharmacological activation of integrin CD11b/CD18 (αMβ2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes an active, higher-affinity conformation of the ligand-binding I/A-domain (CD11b αA-domain). In vitro, this mutation increased adhesion of knock-in neutrophils to fibrinogen and decreased neutrophil chemotaxis to a formyl-Met-Leu-Phe gradient. In vivo, CD11bI332G animals showed a reduction in recruitment of neutrophils and macrophages in a model of sterile peritonitis. This genetic activation of CD11b also protected against development of atherosclerosis in the setting of hyperlipidemia via reduction of macrophage recruitment into atherosclerotic lesions. Thus, our animal model of constitutive genetic activation of CD11b can be a useful tool for the study of integrin activation and its potential contribution to modulating leukocyte recruitment and alleviating different inflammatory diseases.
Collapse
Affiliation(s)
- Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Xiaobo Li
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612
| | - Gioser Ramos-Echazabal
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Hafeez Faridi
- Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, Chicago, IL 60612; and
| | - Zachary M Zigmond
- Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Nieves Santos Falcon
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Diana R Hernandez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Serene A Shehadeh
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Omaida C Velazquez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Vineet Gupta
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612;
| | - Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136;
| |
Collapse
|
|
46
|
Hajishengallis G, Chavakis T, Lambris JD. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000 2020; 84:14-34. [PMID: 32844416 DOI: 10.1111/prd.12331] [Citation(s) in RCA: 241] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent advances indicate that periodontitis is driven by reciprocally reinforced interactions between a dysbiotic microbiome and dysregulated inflammation. Inflammation is not only a consequence of dysbiosis but, via mediating tissue dysfunction and damage, fuels further growth of selectively dysbiotic communities of bacteria (inflammophiles), thereby generating a self-sustained feed-forward loop that perpetuates the disease. These considerations provide a strong rationale for developing adjunctive host-modulation therapies for the treatment of periodontitis. Such host-modulation approaches aim to inhibit harmful inflammation and promote its resolution or to interfere directly with downstream effectors of connective tissue and bone destruction. This paper reviews diverse strategies targeted to modulate the host periodontal response and discusses their mechanisms of action, perceived safety, and potential for clinical application.
Collapse
Affiliation(s)
- George Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
47
|
Gaashan MM, Al-Mubarak AIA, Hussen J. Leukocyte populations and their cell adhesion molecules expression in newborn dromedary camel calves. Vet World 2020; 13:1863-1869. [PMID: 33132598 PMCID: PMC7566236 DOI: 10.14202/vetworld.2020.1863-1869] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/31/2020] [Indexed: 12/25/2022] Open
Abstract
Background and Aim Different properties of the newborn immune system have been characterized in many species. For the newborn camel calf, however, the phenotype and composition of blood leukocytes have so far not been evaluated. The current study aimed to analyze the distribution of leukocyte subpopulations and their expression pattern of cell adhesion molecules in newborn and adult dromedary camels. Materials and Methods Blood samples were collected from 17 newborn camel calves and 32 adult camels. For each sample, total leukocytes were separated and analyzed for their composition and cell adhesion molecules expression by flow cytometry. Results In comparison to adult camels, newborn camel calves had higher leukocyte numbers and higher numbers of neutrophils, monocytes, and lymphocytes but lower numbers of eosinophils in their blood. Among the lymphocyte populations in calves, the fractions of B cells and γδ T cells were elevated when compared to adults, whereas CD4-positive T cells were reduced. The comparison between camel calves and adult camels revealed significantly lower expression of the cell adhesion molecules CD11a, CD11b, and CD18 on granulocytes, monocytes, and lymphocytes in calves. Conclusion Newborn camel calves show a distinct composition and phenotype pattern of blood leukocytes when compared to adult camels. The observed rise in many leukocyte populations in calf blood may be due to reduced migratory activity in calf leukocyte populations.
Collapse
Affiliation(s)
- Muaadh M Gaashan
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Abdullah I A Al-Mubarak
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Jamal Hussen
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| |
Collapse
|
|
48
|
Lin R, Zhang Y, Pradhan K, Li L. TICAM2-related pathway mediates neutrophil exhaustion. Sci Rep 2020; 10:14397. [PMID: 32873853 PMCID: PMC7463027 DOI: 10.1038/s41598-020-71379-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Pathogenic inflammation and immune suppression are the cardinal features that underlie the pathogenesis of severe systemic inflammatory syndrome and sepsis. Neutrophil exhaustion may play a key role during the establishment of pathogenic inflammation and immune suppression through elevated expression of inflammatory adhesion molecules such as ICAM1 and CD11b as well as immune-suppressors such as PD-L1. However, the mechanism of neutrophil exhaustion is not well understood. We demonstrated that murine primary neutrophils cultured in vitro with the prolonged lipopolysaccharides (LPS) stimulation can effectively develop an exhaustive phenotype resembling human septic neutrophils with elevated expression of ICAM1, CD11b, PD-L1 as well as enhanced swarming and aggregation. Mechanistically, we observed that TICAM2 is involved in the generation of neutrophil exhaustion, as TICAM2 deficient neutrophils have the decreased expression of ICAM1, CD11b, PD-L1, and the reduced aggregation following the prolonged LPS challenge as compared to wild type (WT) neutrophils. LPS drives neutrophil exhaustion through TICAM2 mediated activation of Src family kinases (SFK) and STAT1, as the application of SFK inhibitor Dasatinib blocks neutrophil exhaustion triggered by the prolonged LPS challenge. Functionally, TICAM2 deficient mice were protected from developing severe systemic inflammation and multi-organ injury following the chemical-induced mucosal damage. Together, our data defined a key role of TICAM2 in facilitating neutrophil exhaustion and that targeting TICAM2 may be a potential approach to treating the severe systemic inflammation.
Collapse
Affiliation(s)
- RuiCi Lin
- Translational Biology, Medicine, and Health Graduate Program, Virginia Tech, Blacksburg, VA, 24061, USA
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Yao Zhang
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Kisha Pradhan
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Liwu Li
- Translational Biology, Medicine, and Health Graduate Program, Virginia Tech, Blacksburg, VA, 24061, USA.
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA.
| |
Collapse
|
|
49
|
Niu L, Luo SS, Xu Y, Wang Z, Luo D, Yang H, Li W, He J, Zhong XL, Liu ZH, Zeng JY, Cao WY, Wan W. The critical role of the hippocampal NLRP3 inflammasome in social isolation-induced cognitive impairment in male mice. Neurobiol Learn Mem 2020; 175:107301. [PMID: 32882398 DOI: 10.1016/j.nlm.2020.107301] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 01/08/2023]
Abstract
Early life stress exerts detrimental effects on cognitive function, but the mechanism by which this occurs is unknown. The NLRP3 inflammasome-mediated inflammatory response has emerged as a prominent contributor to cognitive impairment induced by chronic stress. In the present study, we showed that 8-week chronic social isolation (SI) led to cognitive impairment in mice, remarkably increasing expression of the hippocampal NLRP3 inflammasome. Furthermore, the 8-week SI procedure significantly increased the levels of hippocampal IL-1β and IL-18 without significant alteration of the level of serum IL-1β, suggesting a central mechanism for IL-1β-related CNS inflammation. Moreover, inflammatory microglial and expression of AMPAR were reduced in the hippocampus of SI mice. Minocycline is an antibiotic that limits microglia responses, and previous study also showed that minocycline could prevent stress-induced pro-inflammatory cytokine expression in the brain. Our experiment found that minocycline improved cognitive behavior in SI mice. Minocycline also prevented expression of the hippocampal NLRP3 inflammasome, indicating that microglia might be the primary contributor to SI-induced hippocampal NLRP3 inflammasome activation. Furthermore, alterations in SI mice were also restored by chronic treatment with the NLRP3 inhibitor MCC950. These results indicate that the microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to social isolation and that specific NLRP3 inflammasome inhibition using MCC950 may represent a promising therapeutic approach for early stress induced cognitive impairment.
Collapse
Affiliation(s)
- Lei Niu
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China; Liuyang Traditional Chinese Medicine Hospital, 421001 Liuyang, Hunan, China
| | - Shi Shi Luo
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Yang Xu
- Institute of Neuroscience, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Zhen Wang
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Dan Luo
- Department of Pathology, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Hui Yang
- Department of Pathology, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Wei Li
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Jie He
- Department of Pathology, In Tropical Environment Of Hainan Province, Hainan Medical University, Haikou 571199, China; Department of Pathology, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Xiao Lin Zhong
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, 421001 Hengyang, Hunan, China
| | - Zheng Hai Liu
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Jia Yu Zeng
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Wen Yu Cao
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
| | - Wei Wan
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China; Key Laboratory Of Brain Science Research & Transformation In Tropical Environment Of Hainan Province, Hainan Medical University, Haikou 571199, China.
| |
Collapse
|
|
50
|
Baiula M, Greco R, Ferrazzano L, Caligiana A, Hoxha K, Bandini D, Longobardi P, Spampinato S, Tolomelli A. Integrin-mediated adhesive properties of neutrophils are reduced by hyperbaric oxygen therapy in patients with chronic non-healing wound. PLoS One 2020; 15:e0237746. [PMID: 32810144 PMCID: PMC7433869 DOI: 10.1371/journal.pone.0237746] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/31/2020] [Indexed: 12/30/2022] Open
Abstract
In recent years, several studies suggested that the ability of hyperbaric oxygen therapy (HBOT) to promote healing in patients with diabetic ulcers and chronic wounds is due to the reduction of inflammatory cytokines and to a significant decrease in neutrophils recruitment to the damaged area. α4 and β2 integrins are receptors mediating the neutrophil adhesion to the endothelium and the comprehension of the effects of hyperbaric oxygenation on their expression and functions in neutrophils could be of great importance for the design of novel therapeutic protocols focused on anti-inflammatory agents. In this study, the α4 and β2 integrins' expression and functions have been evaluated in human primary neutrophils obtained from patients with chronic non-healing wounds and undergoing a prolonged HBOT (150 kPa per 90 minutes). The effect of a peptidomimetic α4β1 integrin antagonist has been also analyzed under these conditions. A statistically significant decrease (68%) in β2 integrin expression on neutrophils was observed during the treatment with HBO and maintained one month after the last treatment, while α4 integrin levels remained unchanged. However, cell adhesion function of both neutrophilic integrins α4β1 and β2 was significantly reduced 70 and 67%, respectively), but α4β1 integrin was still sensitive to antagonist inhibition in the presence of fibronectin, suggesting that a combined therapy between HBOT and integrin antagonists could have greater antinflammatory efficacy.
Collapse
Affiliation(s)
- Monica Baiula
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | - Roberto Greco
- Department of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum -University of Bologna, Bologna, Italy
| | - Lucia Ferrazzano
- Department of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum -University of Bologna, Bologna, Italy
| | - Alberto Caligiana
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | | | | | | | - Santi Spampinato
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | - Alessandra Tolomelli
- Department of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum -University of Bologna, Bologna, Italy
| |
Collapse
|