Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin–induced hemolytic-uremic syndrome in mice

Pirschel, Wiebke; Mestekemper, Antonio N.; Wissuwa, Bianka; Krieg, Nadine; Kröller, Sarah; Daniel, Christoph; Gunzer, Florian; Tolosano, Emanuela; Bauer, Michael; Amann, Kerstin; Heinemann, Stefan; Coldewey, Sina M.

doi:10.1016/j.kint.2021.12.024

Cited by 17 publications

(6 citation statements)

References 69 publications

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“…In some iron-overload disease, iron promotes neutrophils recruitment and inflammation by upregulating IL-1β ( 36 ). In Shiga-toxin-induced hemolytic–uremic syndrome, heme-scavenging proteins, haptoglobin, attenuated kidney platelet deposition and neutrophil recruitment, revealing the potential correlation between iron and neutrophil recruitment ( 37 ).…”

Section: Iron Regulates Neutrophils Recruitment and Inflammationmentioning

confidence: 99%

Iron Metabolism and Immune Regulation

et al. 2022

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Iron is a critical element for living cells in terrestrial life. Although iron metabolism is strictly controlled in the body, disturbance of iron homeostasis under certain type of condition leads to innate and adaptive immune response. In innate immunity, iron regulates macrophage polarizations, neutrophils recruitment, and NK cells activity. In adaptive immunity, iron had an effect on the activation and differentiation of Th1, Th2, and Th17 and CTL, and antibody response in B cells. In this review, we focused on iron and immune regulation and listed the specific role of iron in macrophage polarization, T-cell activation, and B-cells antibody response. In addition, correlations between iron and several diseases such as cancer and aging degenerative diseases and some therapeutic strategies targeting those diseases are also discussed.

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Section: Iron Regulates Neutrophils Recruitment and Inflammationmentioning

confidence: 99%

Iron Metabolism and Immune Regulation

et al. 2022

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“…Thereby, the secretion of interleukin-8 or monocyte chemotactic protein 1 of the Stx-affected cells generates an inflammatory environment, while simultaneously enhancing immune cell adhesion and their migration into renal tissue (33-35). Therefore, it is not surprising that recruitment of macrophages, neutrophils and other immune cells is well documented in murine kidneys of our HUS model as well as in HUS patients (18,19,36). Interestingly, binding of Stx to neutrophils prolongs their lifespan, increases reactive oxygen species production and neutrophil extracellular trap formation and thereby intensifying the inflammatory process, indicating neutrophils are an important player in HUS pathophysiology (37).…”

Section: Discussionmentioning

confidence: 82%

“…Body weight was monitored daily and disease progression was evaluated three times daily using an established HUS score (Supplementary Table S1), in which the disease severity was categorized from 1 = no signs of illness to 5 = dead. Survival was monitored up to day 7 using humane endpoints (18,19). Animals were exsanguinated in deep anesthesia (100 mg/kg ketamine; 10 mg/kg xylazine) and perfused with 0.9% NaCl.…”

Section: Animal Experiments and Study Designmentioning

confidence: 99%

Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome

Kröller

Wissuwa²,

Dennhardt³

et al. 2023

Front. Immunol.

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Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing Escherichia coli. Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro-inflammatory response. To date, therapy is limited to organ-supportive strategies. Bruton’s tyrosine kinase (BTK) plays a pivotal role in recruitment and function of immune cells and its inhibition was recently shown to improve renal function in experimental sepsis and lupus nephritis. We hypothesized that attenuating the evoked immune response by BTK-inhibitors (BTKi) ameliorates outcome in HUS. We investigated the effect of daily oral administration of the BTKi ibrutinib (30 mg/kg) and acalabrutinib (3 mg/kg) in mice with Stx-induced HUS at day 7. After BTKi administration, we observed attenuated disease progression in mice with HUS. These findings were associated with less BTK and downstream phospholipase-C-gamma-2 activation in the spleen and, subsequently, a reduced renal invasion of BTK-positive cells including neutrophils. Only ibrutinib treatment diminished renal invasion of macrophages, improved acute kidney injury and dysfunction (plasma levels of NGAL and urea) and reduced hemolysis (plasma levels of bilirubin and LDH activity). In conclusion, we report here for the first time that BTK inhibition attenuates the course of disease in murine HUS. We suggest that the observed reduction of renal immune cell invasion contributes – at least in part – to this effect. Further translational studies are needed to evaluate BTK as a potential target for HUS therapy to overcome currently limited treatment options.

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“…While HPX deficiency promotes AKI in sickle cell mice under hemolytic stress, HPX injection did not alter hemoglobinuria (24, 25). In a Shigatoxin-induced HUS mouse model, HPX knockout mice displayed improved survival and reduced tubular iron deposition compared to wild-type mice (67).…”

Section: Hemopexin Replenishment Therapymentioning

confidence: 93%

“…However, HPX does not always act as a protective factor in infection-related hemolysis. For instance, in a mouse model of Shiga toxin-induced hemolytic-uremic syndrome (HUS), HPX deficiency was protective in resolving HUS pathology (67). HPX -/mice exhibited higher survival rates when challenged with Shiga toxin, with reduced renal inflammation characterized by decreased macrophage and neutrophil recruitment and C3c deposition [66].…”

Section: Hemopexin's Role In Malaria Hemolyticuremic Syndrome and Den...mentioning

confidence: 99%

Double-edged functions of hemopexin in hematological related diseases: from basic mechanisms to clinical application

Li,

Chen,

Wang

et al. 2023

Front. Immunol.

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It is now understood that hemolysis and the subsequent release of heme into circulation play a critical role in driving the progression of various diseases. Hemopexin (HPX), a heme-binding protein with the highest affinity for heme in plasma, serves as an effective antagonist against heme toxicity resulting from severe acute or chronic hemolysis. In the present study, changes in HPX concentration were characterized at different stages of hemolytic diseases, underscoring its potential as a biomarker for assessing disease progression and prognosis. In many heme overload-driven conditions, such as sickle cell disease, transfusion-induced hemolysis, and sepsis, endogenous HPX levels are often insufficient to provide protection. Consequently, there is growing interest in developing HPX therapeutics to mitigate toxic heme exposure. Strategies include HPX supplementation when endogenous levels are depleted and enhancing HPX’s functionality through modifications, offering a potent defense against heme toxicity. It is worth noting that HPX may also exert deleterious effects under certain circumstances. This review aims to provide a comprehensive overview of HPX’s roles in the progression and prognosis of hematological diseases. It highlights HPX-based clinical therapies for different hematological disorders, discusses advancements in HPX production and modification technologies, and offers a theoretical basis for the clinical application of HPX.

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Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin–induced hemolytic-uremic syndrome in mice

Cited by 17 publications

References 69 publications

Iron Metabolism and Immune Regulation

Iron Metabolism and Immune Regulation

Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome

Double-edged functions of hemopexin in hematological related diseases: from basic mechanisms to clinical application

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