scholarly journals Sphingosine‐1‐phosphate receptor 1 mediates elevated IL‐6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease

2018 ◽  
Vol 32 (5) ◽  
pp. 2855-2865 ◽  
Author(s):  
Shushan Zhao ◽  
Morayo G. Adebiyi ◽  
Yujin Zhang ◽  
Jacob P. Couturier ◽  
Xuegong Fan ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate

Metabolomic Profiles Reveal Sphingosine-1-Phosphate As a Novel Allosteric Modulator of Hemoglobin-Oxygen Affinity and a Key Contributor to Pathophysiology of Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. LBA-3-LBA-3
Author(s):  
Yujin Zhang ◽  
Vladimir Berka ◽  
Wei Wang ◽  
Weiru Zhang ◽  
Chen Ning ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Substantial Reduction ◽  
Allosteric Modulator ◽  
High Morbidity ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate ◽  
Life Threatening ◽  
The Impact

Abstract LBA-3 Sickle cell disease (SCD) is a debilitating hemolytic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was first identified a century ago, we still lack effective mechanism-based safe therapies to treat this disease. Thus, identification of specific molecules triggering sickling, the central pathogenic process of the disease, is extremely important to advance our understanding of the molecular basis for the pathogenesis of SCD and to develop novel therapeutics. Using non-biased metabolomic screening, we found that sphingosine-1-phosphate (S1P) is significantly elevated in the blood of SCD mice. Further analysis revealed that the activity of sphingosine kinase 1 (Sphk1, the enzyme that produces S1P) is significantly elevated in erythrocytes of SCD mice. Chronic treatment of SCD mice with a SphK1 inhibitor significantly attenuated sickling, hemolysis, inflammation and multiple tissue damage by reducing erythrocyte and plasma S1P levels. Erythrocyte S1P levels were further elevated following hypoxia/reoxygenation-induced acute sickle crisis (ASC) in SCD mice and blocking its elevation by a Sphk1 specific inhibitor significantly reduced hallmark features associated with ASC. As with SCD mice, we found that erythrocyte Sphk1 activity and erythrocyte and plasma S1P levels were significantly elevated in humans with SCD compared to normal individuals. Inhibition of SphK1 in cultured primary human erythrocytes isolated from SCD patients inhibited hypoxia-induced elevation of erythrocyte S1P levels and reduced sickling. Thus, we have revealed for the first time that SphK1-mediated S1P elevation in SCD erythrocytes is a key contributor to sickling in SCD and that Sphk1 inhibition can attenuate both acute and chronic sickling events and disease progression. S1P is an important signaling molecule regulating diverse biological processes. Although S1P is predominantly produced and stored in RBCs, nothing was known about the physiological role of S1P in normal RBCs or the pathophysiological role of S1P in SCD until we conducted a metabolomic screen. In an effort to determine the molecular mechanism underlying S1P-induced sickling, we unexpectedly found that S1P directly binds with Hb and results in a reduced Hb-O2 affinity. This finding led us to further discover that 2,3-diphosphoglycerate, another erythrocyte specific allosteric modulator, is required for S1P-mediated allosteric modulation and that these two endogenous heterotropic modulators work cooperatively to induce a substantial reduction in Hb-O2 affinity. Supporting the biochemical and functional findings, molecular modeling predicts that S1P binds near the water filled central cavity of HbA at a site that is different from the Hb-2,3-DPG binding site. Thus, our discovery adds a significant new chapter to erythrocyte physiology by revealing S1P is a novel allosteric modulator of Hb-O2 affinity and also providing a mechanism underlying S1P-mediated sickling by promoting the formation of deoxyHbS. Thus, the work reported here could be the foundation leading to future human trials and a possible therapy for SCD, a life-threatening hemolytic disorder for which the current treatment is extremely limited. The significance of our findings extends well beyond SCD. Our findings reveal a previously unrecognized important role for S1P in erythrocyte physiology and indicate a new concept for the regulation of O2 release from Hb under normal and sickle cell disease conditions. For SCD, elevated S1P is detrimental because reduced Hb-O2 affinity leads to more deoxygenation of HbS, increased sickling and subsequent multiple life-threatening complications. However, for normal erythrocytes, elevated S1P is likely beneficial by decreasing Hb-O2 affinity allowing for more O2 release to hypoxic tissues. Thus, for humans with normal Hb, if elevated S1P can induce O2 release to hypoxic tissues it may be a novel therapeutic target for a range of disorders, from chronic heart failure to diabetic retinopathy, traumatic blood loss, pulmonary disease and even cancer. In this way our findings reveal important novel opportunities to treat and prevent not only SCD but also multiple cardiovascular and pulmonary diseases associated with hypoxia. Thus, the impact of our novel finding is significant and enormous. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Persistence of Chronic Inflammation Despite Years of Transfusion Program in SCD Patients: Changing Red Blood Cells Is Not Sufficient to Treat Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 764-764
Author(s):  
Abdoul Karim Dembele ◽  
Patricia Hermand-Tournamille ◽  
Florence Missud ◽  
Emmanuelle Lesprit ◽  
Malika Benkerrou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Blood Cells ◽  
Healthy Controls ◽  
Cell Disease ◽  
The Impact

Abstract Sickle cell disease (SCD) is a severe hemoglobinopathy due to abnormal hemoglobin S (HbS). Although red blood cell dysfunction is at the core of the SCD pathophysiology, several studies have highlighted the important role of inflammatory cells like neutrophils. One of the most serious complications of SCD is cerebral vasculopathy (CV), due to the occlusion of one or more intracranial or cervical arteries. In 1998, the STOP study demonstrated that monthly blood transfusions could reduce the risk of stroke by 90% in children with CV. However, there is large heterogeneity in the evolution of CV under chronic transfusion, sometimes requiring exchange transfusion (ET) program for years without succeeding in healing the CV. The aim of the study is to investigate the impact of long-term transfusion program on neutrophil dysfunction, in order to understand if persistent inflammation could contribute to the non-healing of CV despite HbS permanently below 40%. In SCD children undergoing ET program for at least 1 year, we analysed i)the phenotype of neutrophils with 8 markers of activation/adhesion/ageing, ii)the plasmatic levels of elastase, witnessing the NETose activity of neutrophils, and iii)the ex-vivo adhesion of neutrophils on activated endothelial cells. One hundred and two SCD children with an ET transfusion program for at least 6 months because of CV were included in the study. ET session, carried out every 5 weeks and most of the time by erythrapheresis, reached their biological objectives with a mean HbS rate after ET session of 14.1%, and 35.4% before the next ET session, which means that these patients globally live at an average HbS level of 24% for at least 1 year. We managed to limit iron overload with a mean ferritinemia of 207 µg/L in the whole cohort. Despite these satisfactory results in terms of HbS reduction, the efficiency in curing the CV was modest in accordance with the previously described efficiency of ET program in SCD children: after a mean ET program duration of 4.4 years only 22% of them had an improvement of their CV since the beginning of the ET program, while 60% of them had a stagnation of their CV, and 18% of them worsened their vascular lesions. Considering inflammatory parameters, the patients had persistence of high leukocytosis and high neutrophils count (respective mean of 9810 G/L and 5742 G/L), significantly not different of neutrophils count before inclusion in the ET program. In a random subgroup of 20 patients, we analysed neutrophils phenotype, NETose and endothelial adhesion and compared them to healthy controls and SCD children without ET, treated or not with Hydroxyurea (HU). Overall, we observed as expected an activated, aged and adherent profile of neutrophils from untreated SCD children compared to healthy controls, characterized by an overexpression of CD18/CD11b (p=0,03), CD18/CD11a (p=0,02), CD162 (p=0,01), CD66a (p=0,01) and the ageing markers CD184 high/CD62Llow (p=0,04) as well as a higher plasmatic level of elastase (p=0. 01) and higher adhesion of neutrophils to endothelial cells. All these parameters were alleviated in SCD patients treated with HU. In SCD patient undergoing ET program, we found a similar profile of activated neutrophils to that of untreated SCD patients with a similar expression of activation molecules, high level of elastase and the same increase of neutrophils adhesion to endothelial cells compared to controls, witnessing a persistence of chronic inflammation despites years of ET. Overall, our study highlights that the replacement of sickle red blood cells, even for years, is not sufficient to reverse the deleterious inflammatory phenotype of neutrophils. Given the major role of inflammation in endothelial dysfunction, these could contribute to the persistence of CV in a majority of patients despite efficient ET programs. This raises the question of systematically combining ET program with anti-inflammatory treatment such as HU or P-selectin inhibitors in children with CV. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression

2014 ◽  
Vol 124 (7) ◽  
pp. 3274-3274
Author(s):  
Yujin Zhang ◽  
Vladimir Berka ◽  
Anren Song ◽  
Kaiqi Sun ◽  
Wei Wang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate

High Dickkopf‐1 (DKK‐1) levels are associated with chronic inflammation in children with Sickle Cell Disease

2021 ◽  
Author(s):  
Paola Giordano ◽  
Giovanni Carlo Del Vecchio ◽  
Giovanna Russo ◽  
Viviana Valeria Palmieri ◽  
Laura Piacente ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Cell Disease ◽  
Dickkopf 1

scholarly journals Higher Prevalence of Autoimmune Diseases in Patients with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 982-982
Author(s):  
Man Wai Tang ◽  
Erfan Nur ◽  
Charlotte F.J. Van Tuijn ◽  
Bart J. Biemond
Keyword(s):  
Sickle Cell Disease ◽  
General Population ◽  
Autoimmune Diseases ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Research Funding ◽  
Patient Characteristics ◽  
Organ Damage ◽  
Cell Disease ◽  
Inflammatory State

Abstract Introduction Sickle cell disease (SCD) affects millions of people throughout the world. This is caused by a mutation in the hemoglobin gene resulting in abnormal red blood cells. Patients with SCD are in a state of chronic inflammation that is driven by ongoing hemolysis and ischemia-reperfusion injury due to recurrent vaso-occlusions.(1) It is also known that infections occur more frequently in patients with SCD. Abundant literature support the role of infections, interacting with the immune system as the so-called second hit in the cascade towards development of autoimmune diseases.(2) The chronic inflammation together with genetic predisposition and environmental factors can potentially lead to an auto-inflammatory state and/or disease. Recently, a study has shown a prevalence of autoimmune diseases (AID) of 1,3% in SCD patients between 7 and 17 years of age, although not compared to the general population.(3) Our hypothesis is that due to the chronic inflammation the prevalence of autoimmune diseases in adult patients with SCD are much higher compared to the general population. The aim of the study was to evaluate the proportion of patients with and without an AID. Methods Between 2004 and 2021, patients with SCD aged above 18 were seen at the outpatient clinic at the Amsterdam University Medical Center in Amsterdam. We performed a retrospective study in adult SCD patients to assess the prevalence of AID in SCD. AID was defined as: disease with the presence of autoantibodies and/or auto-reactive lymphocytes becoming involved in inflammation, which develop pathological autoimmunity and finally leads to tissue damage. We have selected 35 most common autoimmune diseases. A total of 338 patients with SCD were eligible and included in the study. The patient characteristics were summarized in Table 1. The previously reported prevalence of the AID in the African-American population was used to compare the prevalence in our study cohort. In addition, risk factors for AID and relation with organ damage was analyzed. Results AID was diagnosed in 36/338 patients with SCD. The prevalence of AID in this cohort is 10,7% compared to 4.7% in the general population (see table 2). There was no difference in patient characteristics (age, sex, genotype) between the SCD patients with or without AID. The BMI was higher in the group of patients with autoimmune diseases, although not statistically significant. In patients with SCD, the most frequent (>1%) diagnosed AID were: sudden deafness (1.8%), hyper- and hypothyroidism (3%) and sarcoidosis (1.2%). With respect to organ damage, a significantly high rate of retinopathy was observed in SCD patients with AID as compared to SCD patients without AID (53% and 29% respectively, p=0.005). Furthermore, a trend towards more frequently microalbuminuria was found in SCD patients with AID 14/36 (39%) as compared to patients without AID 69/302 (23%). Conclusions This study showed for the first time a higher prevalence of autoimmune diseases in adult patients with SCD compared to previous reported in the general population. In patients with AID, a trend towards more microalbuminuria and significantly higher rate of retinopathy were observed. These findings support the hypothesis that the chronic inflammatory state in SCD patients may be related to the development of AID. Further research is needed to find strategies to target the chronic inflammatory state in order to prevent the development of AID. References 1. Nader E, Romana M, Connes P. The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease. Front Immunol. 2020;11:454. 2. Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15. 3. Li-Thiao-Te V, Uettwiller F, Quartier P, Lacaille F, Bader-Meunier B, Brousse V, et al. Coexistent sickle-cell anemia and autoimmune disease in eight children: pitfalls and challenges. Pediatr Rheumatol Online J. 2018;16(1):5. Figure 1 Figure 1. Disclosures Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Biemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Sanquin: Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Kaiqi Sun ◽  
Angelo D’Alessandro ◽  
Mostafa H. Ahmed ◽  
Yujin Zhang ◽  
Anren Song ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Metabolic Reprogramming ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate

scholarly journals Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression

2014 ◽  
Vol 124 (6) ◽  
pp. 2750-2761 ◽  
Author(s):  
Yujin Zhang ◽  
Vladimir Berka ◽  
Anren Song ◽  
Kaiqi Sun ◽  
Wei Wang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate

Metabolomic Profiles Reveal Sphingosine-1-Phosphate As a Novel Allosteric Modulator of Hemoglobin-Oxygen Affinity and a Key Contributor to Pathophysiology of Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. LBA-3-LBA-3
Author(s):  
Yujin Zhang ◽  
Vladimir Berka ◽  
Wei Wang ◽  
Weiru Zhang ◽  
Chen Ning ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Substantial Reduction ◽  
Allosteric Modulator ◽  
High Morbidity ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate ◽  
Life Threatening ◽  
The Impact

Abstract Abstract LBA-3 Sickle cell disease (SCD) is a debilitating hemolytic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was first identified a century ago, we still lack effective mechanism-based safe therapies to treat this disease. Thus, identification of specific molecules triggering sickling, the central pathogenic process of the disease, is extremely important to advance our understanding of the molecular basis for the pathogenesis of SCD and to develop novel therapeutics. Using non-biased metabolomic screening, we found that sphingosine-1-phosphate (S1P) is significantly elevated in the blood of SCD mice. Further analysis revealed that the activity of sphingosine kinase 1 (Sphk1, the enzyme that produces S1P) is significantly elevated in erythrocytes of SCD mice. Chronic treatment of SCD mice with a SphK1 inhibitor significantly attenuated sickling, hemolysis, inflammation and multiple tissue damage by reducing erythrocyte and plasma S1P levels. Erythrocyte S1P levels were further elevated following hypoxia/reoxygenation-induced acute sickle crisis (ASC) in SCD mice and blocking its elevation by a Sphk1 specific inhibitor significantly reduced hallmark features associated with ASC. As with SCD mice, we found that erythrocyte Sphk1 activity and erythrocyte and plasma S1P levels were significantly elevated in humans with SCD compared to normal individuals. Inhibition of SphK1 in cultured primary human erythrocytes isolated from SCD patients inhibited hypoxia-induced elevation of erythrocyte S1P levels and reduced sickling. Thus, we have revealed for the first time that SphK1-mediated S1P elevation in SCD erythrocytes is a key contributor to sickling in SCD and that Sphk1 inhibition can attenuate both acute and chronic sickling events and disease progression. S1P is an important signaling molecule regulating diverse biological processes. Although S1P is predominantly produced and stored in RBCs, nothing was known about the physiological role of S1P in normal RBCs or the pathophysiological role of S1P in SCD until we conducted a metabolomic screen. In an effort to determine the molecular mechanism underlying S1P-induced sickling, we unexpectedly found that S1P directly binds with Hb and results in a reduced Hb-O2 affinity. This finding led us to further discover that 2,3-diphosphoglycerate, another erythrocyte specific allosteric modulator, is required for S1P-mediated allosteric modulation and that these two endogenous heterotropic modulators work cooperatively to induce a substantial reduction in Hb-O2 affinity. Supporting the biochemical and functional findings, molecular modeling predicts that S1P binds near the water filled central cavity of HbA at a site that is different from the Hb-2,3-DPG binding site. Thus, our discovery adds a significant new chapter to erythrocyte physiology by revealing S1P is a novel allosteric modulator of Hb-O2 affinity and also providing a mechanism underlying S1P-mediated sickling by promoting the formation of deoxyHbS. Thus, the work reported here could be the foundation leading to future human trials and a possible therapy for SCD, a life-threatening hemolytic disorder for which the current treatment is extremely limited. The significance of our findings extends well beyond SCD. Our findings reveal a previously unrecognized important role for S1P in erythrocyte physiology and indicate a new concept for the regulation of O2 release from Hb under normal and sickle cell disease conditions. For SCD, elevated S1P is detrimental because reduced Hb-O2 affinity leads to more deoxygenation of HbS, increased sickling and subsequent multiple life-threatening complications. However, for normal erythrocytes, elevated S1P is likely beneficial by decreasing Hb-O2 affinity allowing for more O2 release to hypoxic tissues. Thus, for humans with normal Hb, if elevated S1P can induce O2 release to hypoxic tissues it may be a novel therapeutic target for a range of disorders, from chronic heart failure to diabetic retinopathy, traumatic blood loss, pulmonary disease and even cancer. In this way our findings reveal important novel opportunities to treat and prevent not only SCD but also multiple cardiovascular and pulmonary diseases associated with hypoxia. Thus, the impact of our novel finding is significant and enormous. Disclosures: No relevant conflicts of interest to declare.

S1P Receptor 1-Mediatd Elevated IL-6 Signaling Underlies Chronic Inflammation and Multiple Tissue Damage in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4849-4849
Author(s):  
Yujin Zhang ◽  
Shushan Zhao ◽  
Jacob Couturier ◽  
Rodney E. Kellems ◽  
Dorothy L. Lewis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sickle Cell Disease ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Tissue Damage ◽  
Dependent Manner ◽  
Cell Disease ◽  
Primary Mouse ◽  
S1p Receptor ◽  
The Impact

Abstract Objective-Sphingosine 1 phosphate (S1P) is a biolipid involved in chronic inflammation in multiple inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic genetic disorder associated with severe chronic inflammation. Here we evaluated the impact of S1P in chronic inflammation and underlying mechanisms in SCD. Approach and Results-First, we demonstrated that interfering with S1P receptor signaling by FTY720, a FDA approved drug, significantly reduced systemic and local inflammation without anti-sickling effects. These findings led us to discover that IL-6 was highly elevated in the circulation and that increased S1P signaling via S1P receptors contributed to the induction of IL-6 in SCD mice. Genetic deletion of IL-6 in SCD significantly reduced local and systemic inflammation and multiple tissue damage and kidney dysfunction. Moreover, we determined that elevated IL-6 led to increased macrophage infiltration and elevated S1P1 gene expression in the macrophages of multiple tissues in SCD mice. Mechanistically, we reveled that S1P-S1P1 signaling reciprocally upregulated IL-6 gene expression in primary mouse macrophages in a JAK2-dependent manner. Conclusion-Altogether, we revealed that elevated S1P signaling via S1P1-induced IL-6 is a key signaling network functioning as a malicious positive feed forward loop sustaining inflammation and promoting tissue damage in SCD. Our findings immediately highlight novel therapeutic possibilities. Disclosures No relevant conflicts of interest to declare.

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