A gut feeling to stress enhances neutrophil-mediated vascular occlusion

2020 ◽  
Vol 12 (556) ◽  
pp. eabd4776
Author(s):  
Chiara Giannarelli
Keyword(s):  
Sickle Cell Disease ◽  
Psychological Stress ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Cell Response ◽  
Vascular Occlusion ◽  
Cell Disease

Psychological stress alters TH17 cell response to gut microbiome and triggers acute vascular-occlusion induced by aged-neutrophils in sickle cell disease.

scholarly journals The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255956
Author(s):  
Hassan Brim ◽  
James Taylor ◽  
Muneer Abbas ◽  
Kimberly Vilmenay ◽  
Mohammad Daremipouran ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Tissue Injury ◽  
Organ Damage ◽  
Composition Analysis ◽  
Cell Disease ◽  
Blood Disorder ◽  
Major Player ◽  
Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

scholarly journals Hemolysis Inhibits Humoral B Cell Responses and Modulates Alloimmunization Risk in Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Author(s):  
Mouli Pal ◽  
Weili Bao ◽  
Rikang Wang ◽  
Yunfeng Liu ◽  
Xiuli An ◽  
...  
Keyword(s):  
B Cells ◽  
Sickle Cell Disease ◽  
B Cell ◽  
Sickle Cell ◽  
Cell Response ◽  
Cell Activity ◽  
Immunomodulatory Activity ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
B Cell Response

Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B cell plasmablast/plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas non-alloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were non-responsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B cell response to hemolysis, we found elevated B cell basal levels of DOCK8 and higher HO-1-mediated inhibition of activated B cells in non-alloimmunized compared to alloimmunized SCD patients. To overcome the alloimmunized B cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B cell activity, reversing the resistance to heme suppression in alloimmunized patients. B cell inhibition by quinine only occurred in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B cell response and that B cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. Quinine by restoring B cell heme sensitivity may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.

scholarly journals Biologic Complexity in Sickle Cell Disease: Implications for Developing Targeted Therapeutics

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Beatrice E. Gee
Keyword(s):  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Occlusion ◽  
Current Therapy ◽  
Cell Disease ◽  
Primary Defect ◽  
Relative Contribution ◽  
Hb S

Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstratedin vivobefore investing in expensive and labor-intensive clinical trials.

Microparticles As Biomarkers Of Osteonecrosis Of The Hip In Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2226-2226
Author(s):  
Anne M Marsh ◽  
Raymond Schiffelers ◽  
Ginny Gildengorin ◽  
Frans A Kuypers ◽  
Carolyn Hoppe
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Vascular Occlusion ◽  
Predictive Biomarker ◽  
Acute Chest Syndrome ◽  
Mobility Limitations ◽  
Cell Disease ◽  
The Past ◽  
D Dimer

Abstract Introduction Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) in children. ONFH is a debilitating condition that is associated with mobility limitations, chronic pain, and an impaired quality of life. While the mechanisms that cause ONFH remain unknown, ischemia from recurrent microvascular occlusion is likely to play a role. Vascular occlusion may result directly from obstruction by sickled cells, or indirectly via complex interdependent pathways characterized by sustained endothelial activation, chronic inflammation, and coagulation. Microparticles (MP) are small, cell membrane-derived vesicles generated in response to cellular activation, injury or apoptosis. MPs have emerged as potential modulators of inflammation and thrombosis and have been found to be elevated in patients with ONFH in the general population. Objective This pilot study examined whether microparticle levels in patients with SCD who have ONFH differ from SCD patients without ONFH, as well as healthy African American (AA) controls. Methods Subjects were recruited at their baseline status and were excluded if they had been transfused within the past 30 days, hospitalized for a vaso-occlusive pain episode, acute chest syndrome, fever or surgery within the past 30 days, or had bony lesions of the femur or hip due to causes unrelated to SCD. For MP analysis, whole blood was collected in sodium citrate tubes and centrifuged for 15 minutes at 1500 x g at 20° C to generate platelet poor plasma. Aliquots of the plasma were immediately frozen and stored at -80° C until the time of MP analysis. 300 μl samples were diluted in PBS and centrifuged at 10000 x g for 1hr and the supernatant was centrifuged at 100,000 x g for 2 hr. The pellet was re-suspended in 1 mL of PBS and subjected to nanoparticle-tracking analysis to determine concentration and size. Additional laboratory biomarkers of inflammation and coagulation, including highly-sensitive C-reactive protein (hs-CRP), von Willebrand factor antigen (vWF Ag), tissue factor (TF), and D-dimer were analyzed for differences between groups. Analysis of variance was used to compare MP and biomarker levels between the three groups. The institutional review board at Children's Hospital & Research Center Oakland approved the study protocol and written informed consent was obtained from all participants. Results Characteristics of the 30 subjects enrolled are shown in Table I. Total microparticle levels in ONFH(+) patients were 2.3-fold higher than in ONFH(-) patients, and 2.5-fold higher than in AA controls (Figure 1). Mean MP levels for ONFH(+) patients, ONFH(-) patients, and AA controls were 4.55 x 1010, 1.99 x 1010, and 1.85 x 1010, respectively. Microparticle levels in ONFH(-) SCD patients did not differ from AA controls. There were no statistically significant differences in hsCRP, vWF Ag, TF, or D-dimer levels between the ONFH(-) and ONFH(+) groups. Conclusions The results of this study demonstrate significantly elevated MP levels in individuals with SCD who have ONFH. Additional studies are needed to better understand the mechanistic effects of MPs on the development of ONFH and to determine whether MP levels may be useful as a predictive biomarker for early disease detection. This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease?

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 426-432 ◽  
Author(s):  
Joshua J. Field
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Tissue Injury ◽  
Quality Care ◽  
Vascular Occlusion ◽  
Cellular Adhesion ◽  
Cell Disease ◽  
Inkt Cells ◽  
Cell Therapies ◽  
Sickle Cells

AbstractRecent insights into the pathogenesis of microvascular occlusion downstream of the sickled red cell have revealed new therapeutic targets for sickle cell disease (SCD). After the formation of sickle cells, tissue injury spurs inflammation, which leads to receptor-mediated contacts between sickle cells, leukocytes, and vascular endothelium. Specifically, selectins decelerate sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other cell–cell interactions, ultimately leading to vascular occlusion. Invariant NKT (iNKT) cells, activated during reperfusion, generate a broad inflammatory response, which further increases cellular adhesion and vascular occlusion. Novel therapies are in development that target selectins and iNKT cells to prevent or interrupt the vicious cycle of adhesion and inflammation. Although the therapies hold promise for the treatment of SCD, an underappreciated threat to their development is poor access to care for people with SCD. Unless the majority of people with SCD have access to consistent, high-quality care, they will not have the opportunity to participate in a clinical trial or receive any new therapy, regardless of its efficacy.

Hemoglobin Bound Von Willebrand Factor (HbVWF) Multimers Are Hyperactive and More Prevalent in Patients with Sickle Cell Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3058-3058
Author(s):  
Zhou Zhou ◽  
Hyojeong Han ◽  
Mark M. Udden ◽  
Miguel A. Cruz ◽  
Jing-fei Dong ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Von Willebrand Factor ◽  
Percent Level ◽  
Vascular Occlusion ◽  
Cell Disease ◽  
Normal Individuals ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 3058 Poster Board II-1034 Elevated levels of von Willebrand factor (VWF), especially the ultra-large multimers, play a significant role in the pathogenesis of vascular occlusion in sickle cell disease (SCD) by promoting cell adhesion to the endothelium. Investigating the pathophysiology of vaso-occlusion and thrombosis in SCD, we have recently observed that excessive extracellular-hemoglobin (Hb) in plasma significantly inhibited ADAMTS-13 proteolysis of VWF by binding directly to the enzyme cleavage-site on VWF. Here, we further show that subpopulations of VWF multimers, which are bound to extracellular-Hb, exist in plasma. We have successfully isolated the Hb-bound VWF (HbVWF) multimers from SCD patients' plasma using the Ni-NTA column and quantified by commercial kit. The HbVWF multimers exist in 5 to 6-times less quantity than the Hb-free multimers as measured in SCD patients. Purified HbVWF multimers are mostly uncleavable by recombinant ADAMTS-13 in vitro. These HbVWF multimers are hyper active in agglutinating platelets as detected by ristocetin cofactor (RCof) activity assay, and also hyper adhesive to collagen type-III compared to the Hb-free multimers. The HbVWF multimers exists in about 2-fold more quantity in SCD patients than normal individuals [mean percent level ± SE, 8.1±1.8 (individual mean 6 – 11) vs. 16.6±3 (12 – 21), P <0.001; n=10]. Using another sandwich-ELISA assay we have reexamined the HbVWF levels, which showed a similar pattern as above. Further, the increased level of HbVWF multimers exists parallely with an elevated RCof activity of plasma VWF [mean percent activity ± SE, 100.4±15.1 (78 – 124) vs. 132.9±11.4, (109 – 149), P <0.001] and high extracellular-Hb levels [mean mg/L ± SE, 59±6.5 (42 – 96) vs. 281.5±71.7 (184 – 410), P <0.001] in plasma of SCD patients compared to normal individuals. Therefore, we believe that these hyperactive HbVWF multimers play a crucial role in cell adhesion, vascular occlusion and thrombosis in SCD. Also, we speculate that this mechanism is not only limited in SCD, but also occurred in other pathophysiological conditions associated with severe intravascular hemolysis. Disclosures No relevant conflicts of interest to declare.

MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease

2015 ◽  
Vol 30 (3) ◽  
pp. 1171-1186 ◽  
Author(s):  
Yulin Zhao ◽  
Evan A. Schwartz ◽  
Gregory M. Palmer ◽  
Rahima Zennadi
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Models ◽  
Sickle Cell ◽  
Vascular Occlusion ◽  
Cell Disease

scholarly journals Spontaneous development of cerebrovascular pathology and microinfarcts in a mouse model of sickle cell disease

2017 ◽  
Author(s):  
Hyacinth I. Hyacinth ◽  
Cortney L. Sugihara ◽  
Thomas L. Spencer ◽  
David R. Archer ◽  
Andy Y. Shih
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Complications ◽  
Vascular Occlusion ◽  
Vessel Diameter ◽  
Cell Disease ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Vessel Tortuosity

ABSTRACTStroke is a dramatic complication of sickle cell disease (SCD) and is associated with aneurysms, moya moya, intravascular thrombi, cerebral hyperemia and increased vessel tortuosity. We show that aged SCD mice spontaneously develop the characteristics features of cerebral vasculopathy seen in human SCD. Thirteen month old Townes SCD mice and age-matched controls had a cranial windows implanted over the somatosensory cortex. Cortical capillaries were imaged using in vivo two-photon microscopy after the blood plasma was labeled with a fluorescent dye. Results showed that SCD mice compared to controls, had significantly higher red blood cell (RBC) velocity and capillary vessel diameter. SCD mice also had a significantly higher number of occlusive events in the capillary bed, resulting in more stalling of RBC flow. Microvascular topology was also altered, as SCD mice had significantly higher vessel tortuosity and shorter capillary branch lengths. Finally, post-mortem analyses revealed a greater number of cortical microinfarcts, likely caused by vascular occlusion since local tissue hypoxia and blood-brain barrier leakage was prominent. We concluded that aged Townes sickle cell mice spontaneously develop SCD-associated cerebral vasculopathy, and that in vivo two-photon imaging is a powerful approach to investigate the mechanisms of vascular complications in SCD.

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