Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells

Sartain, Sarah E.; Turner, Nancy A.; Moake, Joel L.

doi:10.1074/jbc.ra118.002639

Cited by 42 publications

(42 citation statements)

References 80 publications

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“…These parameters are, respectively, an acute phase protein and a surrogate marker of dehydration and have been repeatedly associated with adverse outcomes in STEC-HUS patients ( 43 – 45 ). In our study, however, these laboratory markers did not significantly affect the development of CNS involvement in the multivariate model, probably due to the key role of alternative pathway activation in the onset of thrombotic microangiopathy onto brain microvascular endothelial cells ( 46 , 47 ).…”

Section: Discussioncontrasting

confidence: 80%

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

et al. 2020

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Background: The correlation between the severity of hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) and involvement of the complement system has been examined in a small number of studies, with conflicting results. In the present study, we investigated whether serum C3 levels on admission are associated with neurologic involvement. Methods: To this purpose, 68 consecutive STEC-HUS patients were recruited and main clinical and laboratory variables ad hospital admission were compared between those with or without neurologic involvement. Results: STEC-HUS patients who developed neurologic involvement (NI) showed significant higher leukocyte count, C-reactive protein and hemoglobin, and lower sodium levels as compared with those without. Interestingly, baseline serum levels of C3 were significantly lower in patients with NI as compared with those without (p < 0.001). Moreover, when stratified according to need of Eculizumab rescue therapy due to severe NI, patients treated with this drug showed baseline C3 serum levels significantly lower than those who were not (p < 0.001). Low C3 was independent risk factor for NI in our patients' population when entered as covariate in a multivariate logistic regression analysis including other major variables previously proposed as possible predictors of poor prognosis in STEC-HUS (for instance, leukocyte count, c-reactive protein, sodium levels) (HR 6.401, 95%CI 1.617-25.334, p = 0.008 for C3). To underline the role of complement in the worsening of STEC-HUS patients' clinical conditions and outcomes, all patients were divided into two groups according to the baseline lower vs. normal serum levels of C3 and the main data on care needs were assessed. Interestingly more patients with lower C3 serum levels required renal replacement therapy (p = 0.024), anti-hypertensive therapy (p = 0.011), Intensive Care Unit admission (p = 0.009), and longer hospitalization (p = 0.003), thus displaying Netti et al. C3 and Severe Neurologic STEC-HUS significantly more severe disease features as compared with those with normal C3 serum levels. Conclusions: Our data suggests that children with STEC-HUS with decreased C3 concentrations at admission are more likely to develop neurologic involvement and are at increased risk of having severe clinical complications.

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Section: Discussioncontrasting

confidence: 80%

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

et al. 2020

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“…Exploring the mRNA expression for Cfh in the kidney showed that the expression was identical in the WT and hepatoFH −/− mice and was not affected by PHZ injection (Figure 5B). Exploring of FH staining in mouse kidney has been tricky and previous studies failed to detect it despite the clear evidence for mRNA production by various renal cell populations (26)(27)(28)(29)(30)(31). The reason for this lack of staining in previous studies vs. the positive staining detected here is unclear and is likely related to the experimental conditions.…”

Section: Fh Is Present In the Mouse Kidneymentioning

confidence: 56%

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis

et al. 2020

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Worsening of acute tubular necrosis in the hepatoFH −/− mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.

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“…Recent investigations have reported that the vascular endothelium also plays an important role in modulating the activation and differentiation of B‐ and T‐cells 3‐5 . The expression of the complement anaphylatoxin receptors C3aR and C5aR1 has been documented in several different types of vascular endothelium from tissues and cells from human as well as from other species 48‐51 . However, their significance and overall impact on endothelial cellular function remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

In response to complement anaphylatoxin peptides C3a and C5a, human vascular endothelial cells migrate and mediate the activation of B‐cells and polarization of T‐cells

Shivshankar

Mueller‐Ortiz

et al. 2020

FASEB j.

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The vascular endothelium has been discovered in the past several years to be important in shaping the cellular immune response. During the immune response the vascular endothelium is constantly perturbed by biologically potent molecules, including the complement activation peptides, C3a and C5a. Despite the importance of C3a and C5a in inflammation and immunity, their role in modulating lymphocyte function via activation of vascular endothelial cells is unknown. Accordingly, we investigated the regulated expression of the C3a and C5a receptors (complement anaphylatoxin C3a receptor [C3aR] and complement anaphylatoxin C5a receptor 1 [C5aR1]) on human umbilical vascular endothelial cells (HUVECs) and examined how C3a or C5a activation of HUVECs affects the activation and polarization of lymphatic cells. Our findings demonstrated that C3a and C5a increase C3aR and C5aR1 expression by HUVECs as well as directing their cellular transmigration and spreading through transwell filters. Moreover, C3a‐ or C5a‐stimulated endothelial cells: (1) caused activation of B‐lymphoblasts with significant increase in Fas Ligand (CD95L) (FasL), CD69, and IL‐R1 expression, and (2) skewed T‐lymphoblast cells toward a Th1 subtype, (CD4+/CCR5+) that correlated with significant increase of IFN‐γ. Collectively, these data indicate that C3a and C5a signaling is important in the activation and polarization of lymphocytes as they traffic through the vascular endothelium during the immune response.

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Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells

Cited by 42 publications

References 80 publications

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

Low C3 Serum Levels Predict Severe Forms of STEC-HUS With Neurologic Involvement

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis

In response to complement anaphylatoxin peptides C3a and C5a, human vascular endothelial cells migrate and mediate the activation of B‐cells and polarization of T‐cells

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