scholarly journals Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Masayo Aoki ◽  
Hiroaki Aoki ◽  
Rajesh Ramanathan ◽  
Nitai C. Hait ◽  
Kazuaki Takabe
Keyword(s):  
Immune Cells ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Lymphoid Organs ◽  
Peripheral Tissues ◽  
Physiological Processes ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Cell Processes ◽  
Lymphocyte Egress

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cell processes. It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs) and exported out of cells via transporters such as spinster homolog 2 (Spns2). S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1–5, through a process coined as “inside-out signaling.” The S1P concentration gradient between various tissues promotes S1PR1-dependent migration of T cells from secondary lymphoid organs into the lymphatic and blood circulation. S1P suppresses T cell egress from and promotes retention in inflamed peripheral tissues. S1PR1 in T and B cells as well as Spns2 in endothelial cells contributes to lymphocyte trafficking. FTY720 (Fingolimod) is a functional antagonist of S1PRs that induces systemic lymphopenia by suppression of lymphocyte egress from lymphoid organs. In this review, we summarize previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues. We also discuss the role of S1P-S1PR1 axis in inflammatory diseases and wound healing.

scholarly journals The Role of Sphingolipids in Cancer Immunotherapy

2021 ◽  
Vol 22 (12) ◽  
pp. 6492
Author(s):  
Paola Giussani ◽  
Alessandro Prinetti ◽  
Cristina Tringali
Keyword(s):  
Immune System ◽  
Cancer Cells ◽  
Immune Cells ◽  
Plasma Membranes ◽  
Checkpoint Inhibitors ◽  
Surface Receptors ◽  
Car T ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Lymphocyte Egress

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.

scholarly journals In Vitro and In Vivo Immunomodulator Activities of Allium sativum L.

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Mouna Moutia ◽  
Norddine Habti ◽  
Abdallah Badou
Keyword(s):  
Immune Cells ◽  
Allium Sativum ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Antioxidant Properties ◽  
Allergic Airway Inflammation ◽  
Cytokine Gene Expression

Allium Sativum L. (garlic), which is a species of the onion family, Alliaceae, is one of the most used plants in traditional medicine worldwide. More than 200 chemicals with diverse properties have been found in garlic extracts. Several garlic compounds were suggested to be efficient in improving various pathologies including certain types of cancer. This paper is an overview of data about garlic biological activities in vitro and/or in vivo on immune cells, on the development of certain inflammatory diseases, and on different types of carcinomas and sarcomas. Garlic and its compounds were found to have notable antioxidant properties. Garlic therapeutic potential has also been studied in several inflammatory diseases such as allergic-airway inflammation, inflammatory bowel disease, arthritic rheumatism, and atherosclerosis. Furthermore, garlic was found to be able to maintain the immune system homeostasis and to exhibit beneficial effects on immune cells especially through regulation of proliferation and cytokine gene expression. Finally, we will show how major garlic components such as sulfur compounds and polyphenols might be responsible for the garlic biological activities revealed in different situations. If identified, specific compounds present in garlic could potentially be used in therapy.

scholarly journals Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit

2005 ◽  
Vol 201 (2) ◽  
pp. 291-301 ◽  
Author(s):  
Charles G. Lo ◽  
Ying Xu ◽  
Richard L. Proia ◽  
Jason G. Cyster
Keyword(s):  
Lymph Nodes ◽  
Surface Expression ◽  
Lymphoid Organ ◽  
Lymphoid Organs ◽  
White Pulp ◽  
Activated T Cells ◽  
Circulating Lymphocytes ◽  
Sphingosine 1 Phosphate ◽  
Splenic White Pulp ◽  
Lymphocyte Egress

Sphingosine-1-phosphate receptor 1 (S1P1) was recently shown to be required for lymphocyte egress from lymphoid organs. Here we have examined the relationship between S1P1 abundance on the cell and egress efficiency. Using an integrin neutralization approach to separate the processes of entry and exit, we show that pertussis toxin treatment reduces lymphocyte egress from lymph nodes. Retrovirally mediated S1P1 overexpression is sufficient to reduce B cell accumulation in the splenic white pulp and to promote egress of activated T cells from lymph nodes, whereas S1P1+/−cells have reduced lymph node exit efficiency. Furthermore, lymphocyte S1P1 is down-regulated in the blood, up-regulated in lymphoid organs, and down-regulated again in the lymph. We propose that cyclical ligand-induced modulation of S1P1 on circulating lymphocytes contributes to establishing their lymphoid organ transit time.

scholarly journals Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies

Leukemia ◽  
2016 ◽  
Vol 30 (11) ◽  
pp. 2142-2151 ◽  
Author(s):  
C Evangelisti ◽  
C Evangelisti ◽  
F Buontempo ◽  
A Lonetti ◽  
E Orsini ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Therapeutic Potential ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases

scholarly journals Roles of sphingosine-1-phosphate signaling in cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Peng Wang ◽  
Yonghui Yuan ◽  
Wenda Lin ◽  
Hongshan Zhong ◽  
Ke Xu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Signaling Cascades ◽  
Lipid Mediator ◽  
Downstream Signaling ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration

AbstractThe potent pleiotropic lipid mediator sphingosine-1-phosphate (S1P) participates in numerous cellular processes, including angiogenesis and cell survival, proliferation, and migration. It is formed by one of two sphingosine kinases (SphKs), SphK1 and SphK2. These enzymes largely exert their various biological and pathophysiological actions through one of five G protein-coupled receptors (S1PR1–5), with receptor activation setting in motion various signaling cascades. Considerable evidence has been accumulated on S1P signaling and its pathogenic roles in diseases, as well as on novel modulators of S1P signaling, such as SphK inhibitors and S1P agonists and antagonists. S1P and ceramide, composed of sphingosine and a fatty acid, are reciprocal cell fate regulators, and S1P signaling plays essential roles in several diseases, including inflammation, cancer, and autoimmune disorders. Thus, targeting of S1P signaling may be one way to block the pathogenesis and may be a therapeutic target in these conditions. Increasingly strong evidence indicates a role for the S1P signaling pathway in the progression of cancer and its effects. In the present review, we discuss recent progress in our understanding of S1P and its related proteins in cancer progression. Also described is the therapeutic potential of S1P receptors and their downstream signaling cascades as targets for cancer treatment.

scholarly journals Dynamin 2–dependent endocytosis is required for sustained S1PR1 signaling

2014 ◽  
Vol 211 (4) ◽  
pp. 685-700 ◽  
Author(s):  
Tim Willinger ◽  
Shawn M. Ferguson ◽  
João P. Pereira ◽  
Pietro De Camilli ◽  
Richard A. Flavell
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Lymph Nodes ◽  
Knockout Mice ◽  
Lymphoid Organs ◽  
Essential Component ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Lymphocyte Egress ◽  
Dynamin 2

Sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is critical for lymphocyte egress from lymphoid organs. Lymphocytes encounter low S1P concentrations near exit sites before transmigration, yet S1PR1 signaling is rapidly terminated after exposure to S1P. How lymphocytes maintain S1PR1 signaling in a low S1P environment near egress sites is unknown. Here we identify dynamin 2, an essential component of endocytosis, as a novel regulator of T cell egress. Mice with T cell–specific dynamin 2 deficiency had profound lymphopenia and impaired egress from lymphoid organs. Dynamin 2 deficiency caused impaired egress through regulation of S1PR1 signaling, and transgenic S1PR1 overexpression rescued egress in dynamin 2 knockout mice. In low S1P concentrations, dynamin 2 was essential for S1PR1 internalization, which enabled continuous S1PR1 signaling and promoted egress from both thymus and lymph nodes. In contrast, dynamin 2–deficient cells were only capable of a pulse of S1PR1 signaling, which was insufficient for egress. Our results suggest a possible mechanism by which T lymphocytes positioned at exit portals sense low S1P concentrations, promoting their egress into circulatory fluids.

scholarly journals Corrigendum to “Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential”

2016 ◽  
Vol 2016 ◽  
pp. 1-1 ◽  
Author(s):  
Masayo Aoki ◽  
Hiroaki Aoki ◽  
Rajesh Ramanathan ◽  
Nitai C. Hait ◽  
Kazuaki Takabe
Keyword(s):  
Immune Cells ◽  
Therapeutic Potential ◽  
Sphingosine 1 Phosphate

scholarly journals The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1044
Author(s):  
Yun Ge ◽  
Man Huang ◽  
Yong-ming Yao
Keyword(s):  
Immune Cells ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
High Mobility ◽  
Cell Types ◽  
High Mobility Group ◽  
High Mobility Group Protein

High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

scholarly journals S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4391-4399 ◽  
Author(s):  
Nagaja Capitani ◽  
Laura Patrussi ◽  
Livio Trentin ◽  
Orso Maria Lucherini ◽  
Enrica Cannizzaro ◽  
...  
Keyword(s):  
B Cells ◽  
Lymphoid Organs ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Sphingosine 1 Phosphate ◽  
Extended Lifespan ◽  
S1p Receptor ◽  
B Cell Homeostasis ◽  
Lymphocyte Egress ◽  
Extended Survival

Abstract Although intrinsic apoptosis defects are causal to the extended survival of chronic lymphocytic leukemia (CLL) B cells, several lines of evidence support a contribution of the peripheral lymphoid organs and BM microenvironment to the extended lifespan of leukemic B cells. Lymphocyte trafficking is controlled by homing signals provided by stromal cell–derived chemokines and egress signals provided by sphingosine-1-phosphate (S1P). In the present study, we show that expression of S1P1, the S1P receptor responsible for lymphocyte egress, is selectively reduced in CLL B cells with unmutated IGHV. Expression of S1P2, which controls B-cell homeostasis, is also impaired in CLL B cells but independently of the IGHV mutational status. We provide evidence herein that p66Shc, a Shc adaptor family member the deficiency of which is implicated in the apoptosis defects of CLL B cells, controls S1P1 expression through its pro-oxidant activity. p66Shc also controls the expression of the homing receptor CCR7, which opposes S1P1 by promoting lymphocyte retention in peripheral lymphoid organs. The results of the present study provide insights into the regulation of S1P1 expression in B cells and suggest that defective egress caused by impaired S1P1 expression contributes to the extended survival of CLL B cells by prolonging their residency in the prosurvival niche of peripheral lymphoid organs.

scholarly journals Transcriptional Regulation of Sphingosine Kinase 1

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2437
Author(s):  
Joseph Bonica ◽  
Cungui Mao ◽  
Lina M. Obeid ◽  
Yusuf A. Hannun
Keyword(s):  
Transcriptional Regulation ◽  
Inflammatory Diseases ◽  
Second Messengers ◽  
Sphingosine Kinase ◽  
Transcriptional Level ◽  
Sphingosine Kinase 1 ◽  
Micro Rnas ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Expression And Activity

Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally pro-inflammatory, pro-angiogenic, immunomodulatory, and pro-survival; therefore, high SK1 expression and activity have been associated with certain inflammatory diseases and cancer. It is thus important to develop an understanding of the regulation of SK1 expression and activity. In this review, we explore the current literature on SK1 transcriptional regulation, illustrating a complex system of transcription factors, cytokines, and even micro-RNAs (miRNAs) on the post transcriptional level.

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