Macrophage Membrane-Derived Biomimetic Nanoparticles for Treatment of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a severe complication of infectious diseases like Coronavirus disease 2019 (COVID-19) that cause serious damage to public health. Currently, supportive therapy is still the main therapeutic strategy exists for CRS treatment. Here, we show the potential of macrophage membrane-derived biomimetic nanoparticles for CRS treatment. By fusing macrophage membrane on the surface of the PLGA nano core, we constructed biomimetic nanoparticles that inherited the membrane receptors from the "parental" macrophages, enabling the neutralization of CRS-related cytokines. We compared three types of macrophage membranes to screen out more effective biomimetic nanoparticles for CRS treatment. Our results show that M0 macrophage membrane-derived biomimetic nanoparticles could neutralize pro-inflammatory cytokines involved in CRS to the greatest extent and reduce organ damage in a mouse model.

Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines.

RATIONALE: Major depressive disorder (MDD) is a leading cause of disability worldwide but currently prescribed treatments do not adequately ameliorate the disorder in a significant portion of patients. Hence, a better appreciation of its aetiology may lead to the development of novel therapies. OBJECTIVES: In the present study, we have built on our previous findings indicating a role for protease-activated receptor-2 (PAR2) in sickness behaviour to determine whether the PAR2 activator, AC264613, induces behavioural changes similar to those observed in depression-like behaviour. METHODS: AC264613-induced behavioural changes were examined using the open field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), and novel object recognition test (NOR). Whole-cell patch clamping was used to investigate the effects of PAR2 activation in the lateral habenula with peripheral and central cytokine levels determined using ELISA and quantitative PCR. RESULTS: Using a blood-brain barrier (BBB) permeable PAR2 activator, we reveal that AC-264613 (AC) injection leads to reduced locomotor activity and sucrose preference in mice but is without effect in anxiety and memory-related tasks. In addition, we show that AC injection leads to elevated blood sera IL-6 levels and altered cytokine mRNA expression within the brain. However, neither microglia nor peripheral lymphocytes are the source of these altered cytokine profiles. CONCLUSIONS: These data reveal that PAR2 activation results in behavioural changes often associated with depression-like behaviour and an inflammatory profile that resembles that seen in patients with MDD and therefore PAR2 may be a target for novel antidepressant therapies.

Anti-CD52 antibody treatment in murine experimental autoimmune encephalomyelitis induces dynamic and differential modulation of innate immune cells in peripheral immune and central nervous systems.

Anti-CD52 antibody (anti-CD52-Ab) leads to a rapid depletion of T and B cells, followed by reconstitution of immune cells with tolerogenic characteristics. However, very little is known about its effect on innate immune cells. In this study, experimental autoimmune encephalomyelitis mice were administered murine anti-CD52-Ab to investigate its effect on dendritic cells and monocytes/macrophages in the periphery lymphoid organs and the central nervous system (CNS). Our data show that blood and splenic innate immune cells exhibited significantly increased expression of MHC-II and costimulatory molecules, which was associated with increased capacity of activating antigen-specific T cells, at first day but not three weeks after five daily treatment with anti-CD52-Ab in comparison with controls. In contrast to the periphery, microglia and infiltrating macrophages in the CNS exhibited reduced expression levels of MHC-II and costimulatory molecules after antibody treatment at both time-points investigated when compared to controls. Furthermore, the transit response of peripheral innate immune cells to anti-CD52-Ab treatment was also observed in the lymphocyte-deficient SCID mice, suggesting the changes are not a direct consequence of the mass depletion of lymphocytes in the periphery. Our study demonstrates a dynamic and tissue-specific modulation of the innate immune cells in their phenotype and function following the antibody treatment. The findings of differential modulation of the microglia and infiltrating macrophages in the CNS in comparison with the innate immune cells in the peripheral organs support the CNS-specific beneficial effect of alemtuzumab treatment on inhibiting neuroinflammation in multiple sclerosis patients.

Increased Levels of IL-16 in the Central Nervous System during Neuroinflammation Are Associated with Infiltrating Immune Cells and Resident Glial Cells.

Interleukin (IL)-16, a CD4+ immune cell specific chemoattractant cytokine, has been shown to be involved in the development of multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). While immune cells such as T cells and macrophages are reported to be the producers of IL-16, the cellular source of IL-16 in the CNS is less clear. This study investigates the correlation of IL-16 expression levels in the CNS with the severity of neuroinflammation and determines the phenotype of cells which produce IL-16 in the CNS of experimental autoimmune encephalomyelitis (EAE) mice. Our data show that IL-16 expression is significantly increased in the brain and spinal cord tissues of EAE mice compared to phosphate buffered saline (PBS) immunised controls. Dual immunofluorescence staining reveals that the significantly increased IL-16+ cells in the CNS lesions of EAE mice are likely to be the CD45+ infiltrating immune cells such as CD4+ or F4/80+ cells and the CNS resident CD11b+ microglia and GFAP+ astrocytes, but not NeuN+ neurons. Our data suggest cytokine IL-16 is closely involved in EAE pathology as evidenced by its increased expression in the glial and infiltrating immune cells, which impacts the recruitment and activation of CD4+ immune cells in the neuroinflammation.

Clinical Characteristics and Abnormal Parameters Evolution in Patients With Novel Coronavirus Infection: A Case Series of 272 Cases in Guangzhou.

OBJECTIVE: The aim of this study was to present the clinical characteristics and dynamic changes in laboratory parameters of the coronavirus disease 2019 (COVID-19) in Guangzhou, and explore the probable early warning indicators of disease progression. METHOD: We enrolled all the patients diagnosed with COVID-19 in the Guangzhou No. 8 People's Hospital. The patients' demographic and epidemiologic data were collected, including chief complaints, lab results, and imaging examination findings. RESULTS: The characteristics of the patients in Guangzhou are different from those in Wuhan. The patients were younger in age, predominately female, and their condition was not commonly combined with other diseases. A total of 75% of patients suffered fever on admission, followed by cough occurring in 62% patients. Comparing the mild/normal and severe/critical patients, being male, of older age, combined with hypertension, abnormal blood routine test results, raised creatine kinase, glutamic oxaloacetic transaminase, lactate dehydrogenase, C-reactive protein, procalcitonin, D-dimer, fibrinogen, activated partial thromboplastin time, and positive proteinuria were early warning indicators of severe disease. CONCLUSION: The patients outside epidemic areas showed different characteristics from those in Wuhan. The abnormal laboratory parameters were markedly changed 4 weeks after admission, and also were different between the mild and severe patients. More evidence is needed to confirm highly specific and sensitive potential early warning indicators of severe disease.

Clinical applicability of renin-angiotensin system inhibitors in cancer treatment.

The renin-angiotensin system (RAS) regulates physiological functions of the cardiovascular system, kidneys, and other tissues. Various in vivo and in vitro studies have shown that RAS plays a pivotal role in the development of malignant tumors, while several retrospective studies have confirmed that patients undergoing long-term RAS inhibitors (RASi) treatment have a lowered risk of cancer. Moreover, blocking RAS has been shown to inhibit tumor growth, metastasis, and angiogenesis in various experimental models of malignant tumors. Herein, we review the available RASi-related literature and provide an analysis using the scientific atlas software VOSviewer. We observed that recent studies have primarily focused on gene expression, tumor biology, and survival analysis. Through an in-depth data analysis from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx), we identified the impact of AGTR1, an essential component of RAS, on tumors, and we discuss the underlying biological mechanism of RASi. Furthermore, we outline the research progress and potential use of RASi in tumor treatment. Overall, RASi may be a promising adjunct in cancer therapy.

Quantification of computational fluid dynamics simulation assists the evaluation of protection by Gypenosides in a zebrafish pain model.

In recent years, due to its rapid reproduction rate and the similarity of its genetic structure to that of human, the zebrafish has been widely used as a pain model to study chemical influences on behavior. Swimming behaviors are mediated by motoneurons in the spinal cord that drive muscle contractions, therefore a knowledge of internal muscle mechanics can assist the understanding of the effects of drugs on swimming activity. To demonstrate that the technique used in our study can supplement biological observations by quantifying the contribution of muscle effects to altered swimming behaviours, we have evaluated the pain/damage caused by 0.1% acetic acid to the muscle of 5 dpf zebrafish larvae and the effect of protection from this pain/damage with the saponin Gypenosides (GYP) extracted from Gynostemma pentaphyllum. We have quantified the parameters related to muscle such as muscle power and the resultant hydrodynamic force, proving that GYP could alleviate the detrimental effect of acetic acid on zebrafish larvae, in the form of alleviation from swimming debility, and that the muscle status could be quantified to represent the degree of muscle damage due to the acetic acid and the recovery due to GYP. We have also linked the behavioral changes to alteration of antioxidant and inflammation gene expression. The above results provide novel insights into the reasons for pain-related behavioral changes in fish larvae, especially from an internal muscle perspective, and have quantified these changes to help understand the protection of swimming behaviors and internal muscle by GYP from acetic acid-induced damage.

Quantification of the influence of drugs on zebrafish larvae swimming kinematics and energetics.

The use of zebrafish larvae has aroused wide interest in the medical field for its potential role in the development of new therapies. The larvae grow extremely quickly and the embryos are nearly transparent which allows easy examination of its internal structures using fluorescent imaging techniques. Medical treatment of zebrafish larvae can directly influence its swimming behaviours. These behaviour changes are related to functional changes of central nervous system and transformations of the zebrafish body such as muscle mechanical power and force variation, which cannot be measured directly by pure experiment observation. To quantify the influence of drugs on zebrafish larvae swimming behaviours and energetics, we have developed a novel methodology to exploit intravital changes based on observed zebrafish locomotion. Specifically, by using an in-house MATLAB code to process the recorded live zebrafish swimming video, the kinematic locomotion equation of a 3D zebrafish larvae was obtained, and a customised Computational Fluid Dynamics tool was used to solve the fluid flow around the fish model which was geometrically the same as experimentally tested zebrafish. The developed methodology was firstly verified against experiment, and further applied to quantify the fish internal body force, torque and power consumption associated with a group of normal zebrafish larvae vs. those immersed in acetic acid and two neuroactive drugs. As indicated by our results, zebrafish larvae immersed in 0.01% acetic acid display approximately 30% higher hydrodynamic power and 10% higher cost of transport than control group. In addition, 500 µM diphenylhydantoin significantly decreases the locomotion activity for approximately 50% lower hydrodynamic power, whereas 100 mg/L yohimbine has not caused any significant influences on 5 dpf zebrafish larvae locomotion. The approach has potential to evaluate the influence of drugs on the aquatic animal's behaviour changes and thus support the development of new analgesic and neuroactive drugs.

Role of IL-33/ST2 signaling pathway in systemic sclerosis and other fibrotic diseases.

Systemic sclerosis (SSc) is a complex autoimmune disease characterised by fibrosis of the skin and multiple internal organs. Interleukin 33 (IL-33) has recently been investigated as a potential key player in the pathogenesis of SSc and other fibrotic diseases, owing to its effects on tissue fibrosis. Understanding how IL-33 is regulated and how it contributes to the development of fibrosis will be important to elucidate disease pathogenesis and may shed light on new areas for therapeutic development for patients. Here we discuss the recent research progress in our understanding of the role and the underlying mechanisms of IL-33/ST2 signaling pathway in SSc and other fibrotic diseases.

Interleukin-16 inhibits sodium channel function and GluA1 phosphorylation via CD4- and CD9-independent mechanisms to reduce hippocampal neuronal excitability and synaptic activity.

Interleukin 16 (IL-16) is a cytokine that is primarily associated with CD4+ T cell function, but also exists as a multi-domain PDZ protein expressed within cerebellar and hippocampal neurons. We have previously shown that lymphocyte-derived IL-16 is neuroprotective against excitotoxicity, but evidence of how it affects neuronal function is limited. Here, we have investigated whether IL-16 modulates neuronal excitability and synaptic activity in mouse primary hippocampal cultures. Application of recombinant IL-16 impairs both glutamate-induced increases in intracellular Ca2+ and sEPSC frequency and amplitude in a CD4- and CD9-independent manner. We examined the mechanisms underlying these effects, with rIL-16 reducing GluA1 S831 phosphorylation and inhibiting Na+ channel function. Taken together, these data suggest that IL-16 reduces neuronal excitability and synaptic activity via multiple mechanisms and adds further evidence that alternative receptors may exist for IL-16.

Expression and Function of IL-33/ST2 Axis in the Central Nervous System Under Normal and Diseased Conditions.

Interleukin-33 (IL-33) is a well-recognized immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. The abundant expression of IL-33 in brain and spinal cord prompted many scientists to explore its unique role in the central nervous system (CNS) under physiological and pathological conditions. Indeed emerging evidence from over a decade's research suggests that IL-33 acts as one of the key molecular signaling cues coordinating the network between the immune and CNS systems, particularly during the development of neurological diseases. Here, we highlight the recent advances in our knowledge regarding the distribution and cellular localization of IL-33 and its receptor ST2 in specific CNS regions, and more importantly the key roles IL-33/ST2 signaling pathway play in CNS function under normal and diseased conditions.

Failure of the Anti-Inflammatory Parasitic Worm Product ES-62 to Provide Protection in Mouse Models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease.

Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from Acanthocheilonema viteae, a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosphorylcholine (PC) moieties. ES-62 has been found to protect against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus, and airway hyper-responsiveness. Furthermore, novel PC-based synthetic small molecule analogues (SMAs) of ES-62 have recently been demonstrated to show similar anti-inflammatory properties to the parent molecule. In spite of these successes, we now show that ES-62 and its SMAs are unable to provide protection in mouse models of certain autoimmune conditions where other helminth species or their secreted products can prevent disease development, namely type I diabetes, multiple sclerosis and inflammatory bowel disease. We speculate on the reasons underlying ES-62's failures in these conditions and how the negative data generated may help us to further understand ES-62's mechanism of action.

The therapeutic effect of anti-CD52 treatment in murine experimental autoimmune encephalomyelitis is associated with altered IL-33 and ST2 expression levels.

Experimental autoimmune encephalomyelitis (EAE) mice were administered with murine anti-CD52 antibody to investigate its therapeutic effect and whether the treatment modulates IL-33 and ST2 expression. EAE severity and central nervous system (CNS) inflammation were reduced following the treatment, which was accompanied by peripheral T and B lymphocyte depletion and reduced production of various cytokines including IL-33, while sST2 was increased. In spinal cords of EAE mice, while the number of IL-33+ cells remained unchanged, the extracellular level of IL-33 protein was significantly reduced in anti-CD52 antibody treated mice compared with controls. Furthermore the number of ST2+ cells in the spinal cord of treated EAE mice was downregulated due to decreased inflammation and immune cell infiltration in the CNS. These results suggest that treatment with anti-CD52 antibody differentially alters expression of IL-33 and ST2, both systemically and within the CNS, which may indicate IL-33/ST2 axis is involved in the action of the antibody in inhibiting EAE.

Alleviate the J-V hysteresis of carbon-based perovskite solar cells via introducing additional methylammonium chloride into MAPbI3 precursor.

The hysteretic phenomenon commonly exists in the J-V curves of perovskite solar cells with different structures, especially for carbon-based mesoscopic perovskite solar cells without hole-conductor (carbon-based PSCs). By adding moderate amounts of methylammonium chloride (MACl) into MAPbI3 perovskite precursor, we found the J-V hysteresis of carbon-based PSCs could be significantly alleviated and the crystallinity of MAPbI3 perovskite could also be influenced. With the increasing amount of MACl, MAPbI3 perovskite showed better and better crystallinity until the MACl came to 0.45 M. The champion device with 0.45 M of additional MACl exhibited a preferable PCE of 14.27% for reverse-scan (RS) and 14.50% for forward-scan (FS), significantly higher than that of the pristine device (8.74% for RS and 4.80% for FS). What's more, the J-V hysteretic index of the device gradually decreased along with the increasing amount of MACl, and kept at low value even when the crystallinity of MAPbI3 perovskite became poor. Through XRD and PL analysis, we demonstrated that the recombination rate of the accumulated charges at the perovskite/TiO2 interface is the main reason for photocurrent hysteresis in carbon-based PSCs. High quality of perovskite crystals is an important contributing factor for high-performance PSCs with low hysteresis, but there is no necessary correlation between low hysteresis and good crystallinity. This research presents an effective way to fabricate carbon-based PSCs with low-hysteresis, and at the same time, provides evidence for investigating the origin of J-V hysteresis of PSCs.

Effect of sphingosine kinase modulators on interleukin-1ß release, sphingosine 1-phosphate receptor 1 expression and experimental autoimmune encephalomyelitis.

BACKGROUND AND PURPOSE: The sphingosine analogue, FTY720 (GilenyaR ), alleviates clinical disease progression in multiple sclerosis. Here, we variously assessed the effects of an azide analogue of (S)-FTY720 vinylphosphonate (compound 5; a sphingosine kinase 1 activator), (R)-FTY720 methyl ether (ROMe, a sphingosine kinase 2 inhibitor) and RB-020 (a sphingosine kinase 1 inhibitor and sphingosine kinase 2 substrate) on IL-1ß formation, sphingosine 1-phosphate levels and expression of S1P1 receptors. We also assessed the effect of compound 5 and ROMe in an experimental autoimmune encephalomyelitis (EAE) model in mice. EXPERIMENTAL APPROACH: We measured IL-1ß formation by macrophages, sphingosine 1-phosphate levels and expression levels of S1P1 receptors in vitro and clinical score in mice with EAE and the extent of inflammatory cell infiltration into the spinal cord in vivo. KEY RESULTS: Treatment of differentiated U937 macrophages with compound 5, RB-020 or sphingosine (but not ROMe) enhanced IL-1ß release. These data suggest that these compounds might be pro-inflammatory in vitro. However, compound 5 or ROMe reduced disease progression and infiltration of inflammatory cells into the spinal cord in EAE, and ROMe induced a reduction in CD4+ and CD8+ T-cell levels in the blood (lymphopenia). Indeed, ROMe induced a marked decrease in expression of cell surface S1P1 receptors in vitro. CONCLUSION AND IMPLICATIONS: This is the first demonstration that an activator of sphingosine kinase 1 (compound 5) and an inhibitor of sphingosine kinase 2 (ROMe, which also reduces cell surface S1P1 receptor expression) have an anti-inflammatory action in EAE.

MAP kinase phosphatase 2 deficient mice develop attenuated experimental autoimmune encephalomyelitis through regulating dendritic cells and T cells.

Mitogen-activated protein kinase phosphatases (MKPs) play key roles in inflammation and immune mediated diseases. Here we investigated the mechanisms by which MKP-2 modulates central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE). Our results show that MKP-2 mRNA levels in the spinal cord and lymphoid organs of EAE mice were increased compared with naive controls, indicating an important role for MKP-2 in EAE development. Indeed, MKP-2-/- mice developed reduced EAE severity, associated with diminished CNS immune cell infiltration, decreased proinflammatory cytokine production and reduced frequency of CD4+ and CD8+ T cells in spleens and lymph nodes. In addition, MKP-2-/- CD11c+ dendritic cells (DCs) had reduced expression of MHC-II and CD40 compared with MKP-2+/+ mice. Subsequent experiments revealed that CD4+ T cells from naïve MKP-2-/- mice had decreased cell proliferation and IL-2 and IL-17 production relative to wild type controls. Furthermore, co-culture experiments showed that bone marrow derived DCs of MKP-2-/- mice had impaired capability in antigen presentation and T cell activation. While MKP-2 also modulates macrophage activation, our study suggests that MKP-2 is essential to the pathogenic response of EAE, and it acts mainly via regulating the important antigen presenting DC function and T cell activation.

Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system.

Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer's disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination.

A review on continuous-flow microfluidic PCR in droplets: Advances, challenges and future.

Significant advances have been made in developing microfluidic polymerase chain reaction (PCR) devices in the last two decades. More recently, microfluidic microdroplet technology has been exploited to perform PCR in droplets because of its unique features. For example, it can prevent crossover contamination and PCR inhibition, is suitable for single-cell and single-molecule analyses, and has the potential for system integration and automation. This review will therefore focus on recent developments on droplet-based continuous-flow microfluidic PCR, and the major research challenges. This paper will also discuss a new way of on-chip flow control and a rational design simulation tool, which are required to underpin fully integrated and automated droplet-based microfluidic systems. We will conclude with a scientific speculation of future autonomous scientific discoveries enabled by microfluidic microdroplet technologies.

Interleukin-33 predicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, it remains a huge challenge to understand the cellular and molecular mechanisms of the aggressive behavior of EOC cells. Here we investigated the role of an immunomodulatory cytokine IL-33 and its receptor ST2 in mediating the growth and metastasis of EOC. Our data show that both IL-33 and ST2 were highly up-regulated in EOC tumors compared with normal ovary and ovarian benign tumors, and the expression levels were further increased in tumor tissues at the metastatic site. The expression levels of IL-33 and ST2 were positively correlated with the Ki-67 expression, and negatively correlated with the patient survival time. Using EOC cell lines, we observed that cells knocked down of IL-33 gene by siRNA had reduced migratory and invasive potential, while full length human IL-33 (fl-hIL-33) promoted the invasive, migratory and proliferative capacity of EOC cells and this process could be inhibited by IL-33 decoy receptor sST2. Signaling pathway analysis suggested that IL-33 increased the phosphorylation of ERK and JNK which was blocked by sST2. Fl-hIL-33-induced increases in EOC cell migration, invasive potential and proliferation were specifically abrogated by treatment with the ERK inhibitor U0126 while JNK inhibitor SP600125 only disrupted IL-33-induced enhancement of cell viability. Taken together, our data suggest that IL-33/ST2 axis closely associates with poor prognosis of EOC patients, and it promotes ovarian cancer growth and metastasis through regulating ERK and JNK signaling pathways. Thus IL-33/ST2 might be potential prognosis markers and therapeutic targets for EOC patients.

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation.

Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1ß. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed.