Modupe Idowu

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

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD. In murine models of SCD, we demonstrated that elevated erythrocyte sphingosine kinase 1 (SPHK1) underlies sickling and disease progression by increasing S1P levels in the blood. Additionally, we observed elevated SPHK1 activity in erythrocytes and increased S1P in blood collected from patients with SCD and demonstrated a direct impact of elevated SPHK1-mediated production of S1P on sickling that was independent of S1P receptor activation in isolated erythrocytes. Together, our findings provide insights into erythrocyte pathophysiology, revealing that a SPHK1-mediated elevation of S1P contributes to sickling and promotes disease progression, and highlight potential therapeutic opportunities for SCD.

Elevated Adenosine Signaling Via Adenosine A2B Receptor Induces Normal and Sickle Erythrocyte Sphingosine Kinase 1 Activity

Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown. Here we report that adenosine induces SphK1 activity in human and mouse sickle and normal erythrocytes in vitro. Next, using 4 adenosine receptor-deficient mice and pharmacological approaches, we determined that the A2B adenosine receptor (ADORA2B) is essential for adenosine-induced SphK1 activity in human and mouse normal and sickle erythrocytes in vitro. Subsequently, we provide in vivo genetic evidence that adenosine deaminase (ADA) deficiency leads to excess plasma adenosine and elevated erythrocyte SphK1 activity. Lowering adenosine by ADA enzyme therapy or genetic deletion of ADORA2B significantly reduced excess adenosine-induced erythrocyte SphK1 activity in ADA-deficient mice. Finally, we revealed that protein kinase A-mediated extracellular signal-regulated kinase 1/2 activation functioning downstream of ADORA2B underlies adenosine-induced erythrocyte SphK1 activity. Overall, our findings reveal a novel signaling network regulating erythrocyte SphK1 and highlight innovative mechanisms regulating SphK1 activity in normal and SCD.

Atypical thrombotic thrombocytopenic purpura in a middle‐aged woman who presented with a recurrent stroke

An atypical clinical presentation makes TTP diagnosis difficult, which prevents prompt management of TTP. This case highlights the importance of early recognition of TTP in patients with atypical presentations who may not have the expected clinical or laboratory findings. The level of suspicion should be especially high in young and middle-aged patients with strokes or acute coronary syndrome who do not have other risk factors for cardiovascular events. This is particularly so for those patients who have a previous episode of TTP or patients with subtle laboratory abnormalities, which may suggest the potential existence of a thrombotic microangiopathic process.

Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease

Although Lands’ cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands’ cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands’ cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands’ cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras. Human translational studies validated SCD mouse findings and further demonstrated that imbalanced Lands’ cycle induced LysoPC production directly promotes sickling in cultured mouse and human SCD erythrocytes. Mechanistically, we revealed that hypoxia-mediated ERK activation underlies imbalanced Lands’ cycle by preferentially inducing the activity of PLA2 but not LPCAT in human and mouse SCD erythrocytes. Overall, our studies have identified a pathological role of imbalanced Lands’ cycle in SCD erythrocytes, novel molecular basis regulating Lands’ cycle and therapeutic opportunities for the disease.

Isolated mesenteric CD20-positive myeloid sarcoma

Extramedullary manifestations of acute myeloid leukemia (AML) include myeloid sarcomas (MS), which are tumor masses composed of myeloid blasts, with or without maturation, arising in any anatomic location other than the bone marrow (BM) [1]. With only case reports and small retrospective studies available, the incidence of MS is unclear [2, 3]. We present an unusual, diagnostically-challenging case of isolated mesenteric MS without BM involvement [2, 3].

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

Elevated sphingosine 1-phosphate (S1P) is detrimental in Sickle Cell Disease (SCD), but the mechanistic basis remains obscure. Here, we report that increased erythrocyte S1P binds to deoxygenated sickle Hb (deoxyHbS), facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increases deoxyHbS polymerization, sickling, hemolysis and disease progression. Functional studies revealed that S1P and 2,3-BPG work synergistically to decrease both HbA and HbS oxygen binding affinity. The crystal structure at 1.9 Å resolution deciphered that S1P binds to the surface of 2,3-BPG-deoxyHbA and causes additional conformation changes to the T-state Hb. Phosphate moiety of the surface bound S1P engages in a highly positive region close to α1-heme while its aliphatic chain snakes along a shallow cavity making hydrophobic interactions in the “switch region”, as well as with α2-heme like a molecular “sticky tape” with the last 3–4 carbon atoms sticking out into bulk solvent. Altogether, our findings provide functional and structural bases underlying S1P-mediated pathogenic metabolic reprogramming in SCD and novel therapeutic avenues.

Echocardiographic parameters to identify sickle cell patients with cardio-pathology

Sickle cell disease (SCD) affects millions of people and causes chronic hemolytic anemia leading to vasculopathies such as pulmonary hypertension and abnormalities in cardiac function that increase complications and mortality. It is therefore crucial to identify cardiac abnormalities in SCD. We aimed to assess the prevalence of echocardiographic parameters in SCD to help identify cardiopulmonary risk.

Disseminated cytomegalovirus-associated hemophagocytic lymphohistiocytosis in an elderly patient.

TO THE EDITOR: Hemophagocytic lymphohistiocytosis (HLH) is characterized by severe immune activation and deregulation resulting in extreme and often life-threatening inflammation [1]. Adult-onset HLH is rare and fatal. Infectious agents contribute to a major part of the etiology of adult-onset HLH [2,3]. A high degree of clinical suspicion and prompt treatment is required to prevent mortality. We have described an unusual clinical presentation of a case of cytomegalovirus (CMV)-associated HLH with multi-organ involvement.