P-selectin deficiency promotes liver senescence in sickle cell disease mice

Vats, Ravi; Kamiński, Tomasz W.; Ju, Eun-Mi; Brozska, Tomasz; Tutuncuoglu, Egemen; Tejero, Jesús; Novelli, Enrico M.; Sundd, Prithu; Pradhan‐Sundd, Tirthadipa

doi:10.1182/blood.2020009779

Cited by 16 publications

(18 citation statements)

References 24 publications

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“… 32 Previously we 19 and others 33 showed increased expression of leukocytes (monocytes and macrophages) in SCD mouse liver, a phenomenon significantly reduced in SCD mice following P-selectin deletion (SCD; Selp -/- mice). 34 Interestingly, we have also found that chronic P-selectin deficiency in SCD mice exacerbates overall liver senescence and injury. 34 Thus, we hypothesized that the increased liver damage seen in SCD; Selp -/- mice is most likely due to enhanced LSEC senescence.…”

Section: Resultsmentioning

confidence: 71%

Impaired hemoglobin clearance by sinusoidal endothelium promotes vaso-occlusion and liver injury in sickle cell disease

Kaminski,

Katoch,

et al. 2023

haematol

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Sickle cell disease (SCD) is a monogenic disorder that affects 100,000 African Americans and millions of people worldwide. Intra-erythrocytic polymerization of sickle hemoglobin (HbS) promotes erythrocyte sickling, impaired rheology, ischemia and hemolysis, leading to the development of progressive liver injury in SCD. Liver resident macrophages and monocytes are known to enable the clearance of HbS, however, the role of liver sinusoidal endothelial cells (LSECs) in HbS clearance and liver injury in SCD remains unknown. Using real-time intravital (in vivo) imaging in the mice liver as well as flow cytometric analysis and confocal imaging of primary human LSECs, we show for the first time that liver injury in SCD is associated with accumulation of HbS and iron in the LSECs, leading to LSEC senescence. Hb uptake by LSECs was mediated by micropinocytosis. Hepatic monocytes were observed to attenuate LSECsenescence by accelerating HbS clearance in the liver of SCD mice, however, this protection was impaired in P-selectin-deficient SCD mice secondary to reduced monocyte recruitment in the liver. These findings are the first to suggest that LSECs contribute to HbS clearance and HbS induced LSEC-senescence promotes progressive liver injury in SCD mice. Our results provide a novel insight into the pathogenesis of hemolysis induced chronic liver injury in SCD caused by LSEC senescence. Identifying the regulators of LSEC mediated HbS clearance may lead to new therapies to prevent the progression of liver injury in SCD.

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Section: Resultsmentioning

confidence: 71%

Impaired hemoglobin clearance by sinusoidal endothelium promotes vaso-occlusion and liver injury in sickle cell disease

Kaminski,

Katoch,

et al. 2023

haematol

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“…65 However, it is important to note that long-term P-selectin deficiency was shown to reduce immune cell recruitment to the liver increasing cellular senescence and reducing epithelial cell proliferation, thereby impairing the resolution of inflammation in SCD mice. 84 Therefore, the contribution of immune cells to resolution of inflammation during hemolysis should be taken into consideration in long-term therapies in hemolytic diseases.…”

Section: Endothelial Cells As a Target Of Hemolysismentioning

confidence: 99%

Basic Mechanisms of Hemolysis-Associated Thrombo-Inflammation and Immune Dysregulation

Dimitrov

Roumenina

Perrella

et al. 2023

ATVB

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Independent of etiology, hemolytic diseases are associated with thrombosis, inflammation and immune dysregulation, all together contributing to organ damage and poor outcome. Beyond anemia and the loss of the anti-inflammatory functions of red blood cells, hemolysis leads to the release of damage-associated molecular patterns including ADP, hemoglobin, and heme, which act through multiple receptors and signaling pathways fostering a hyperinflammatory-y and hypercoagulable state. Extracellular-free heme is promiscuous damage-associated molecular pattern capable of triggering oxido-inflammatory and thrombotic events by inducing the activation of platelets, endothelial and innate cells as well as the coagulation and complement cascades. In this review, we discuss the main mechanisms by which hemolysis and, in particular, heme, drive this thrombo-inflammatory milieu and discuss the consequences of hemolysis on the host response to secondary infections.

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“…Moreover, blocking receptor binding with antibody targeting the C5a receptor antagonizes upregulation of endothelial adhesion molecules including VCAM-1, ICAM-1, and E-selectin in liver and lungs. It is noteworthy that a P-selectin deficient SCD mouse model revealed that chronic P-selectin deficiency attenuated liver ischemia but did not resolve cellular senescence and reduced epithelial cell proliferation necessary to maintain hepatic homeostasis (74). Complement from human sera has also been shown to stimulate expression of E-selectin in porcine endothelial cells (75).…”

Section: Targeted Therapeutics Against Leukocyte and Platelet Activation In Vaso-occlusive Crisismentioning

confidence: 99%

Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients

et al. 2021

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Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.

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P-selectin deficiency promotes liver senescence in sickle cell disease mice

Cited by 16 publications

References 24 publications

Impaired hemoglobin clearance by sinusoidal endothelium promotes vaso-occlusion and liver injury in sickle cell disease

Impaired hemoglobin clearance by sinusoidal endothelium promotes vaso-occlusion and liver injury in sickle cell disease

Basic Mechanisms of Hemolysis-Associated Thrombo-Inflammation and Immune Dysregulation

Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients

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