Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study

Sundnes, Olav; Ottestad, William; Schjalm, Camilla; Lundbäck, Peter; Poulsen, Lars la Cour; Mollnes, Tom Eirik; Haraldsen, Guttorm; Eken, Torsten

doi:10.1186/s10020-021-00288-1

Cited by 11 publications

(11 citation statements)

References 33 publications

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“…DAMPs are passively released by necrotic cells, but also actively secreted by stressed or activated cells (e.g., high mobility group box protein 1, HMGB1). Elevated levels of HMGB1 ( 42 – 46 ), mtDNA ( 47 – 52 ), heat shock proteins ( 53 – 57 ), Ca 2+ -binding protein S100 ( 58 ), histones ( 59 – 63 ), ATP ( 64 ), interleukin 33 (IL-33) ( 65 ), or IL-1 ( 66 ) have been described after trauma in preclinical and clinical studies. DAMPs activate immune cells via their binding to pattern recognition receptors (PRRs), a group of receptors involved in the innate immune response, and induce the transcription of inflammatory factors ( 67 , 68 ).…”

Section: Traumatic Hemorrhagic Shockmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock

et al. 2021

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Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune–inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.

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Section: Traumatic Hemorrhagic Shockmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock

et al. 2021

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“…This high affinity and fast association rate are consistent with a strong electrostatic complementarity interaction between IL-33 and ST2 [44,45,50,51]. In silico modelling, using measurements of the kinetics of IL-33 release in vivo [4,18,21] and refined IL-33–sST2 binding parameters, also highlighted the importance of a greater than 10 7 M −1 s −1 association rate within the affinity profile to inhibit alarmin activity. In summary, studies of the IL-33–sST2 interaction highlighted the optimal pharmacological and kinetic profile for an anti-IL-33 therapeutic antibody.…”

Section: Discussionmentioning

confidence: 81%

Tozorakimab (MEDI3506): a dual-pharmacology anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction

England

Rees

Scott

et al. 2023

Preprint

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Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products - epidermal growth factor receptor (RAGE-EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107M−1s−1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33redand a fast association rate (8.5 × 107M−1s−1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasingin vitroepithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33redand IL-33oxsignalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

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“…In addition to its central functions, a high level of IL-33 is noted in blood early after TBI in numerous clinical reports ( 12 , 13 , 22 ). The ascending serum IL-33 levels correlate with clinical severity and could be used as a marker for risk assessments and prognosis in TBI patients.…”

Section: Discussionmentioning

confidence: 99%

IL-33/ST2 Axis Protects Against Traumatic Brain Injury Through Enhancing the Function of Regulatory T Cells

Xie

Miao

et al. 2022

Front. Immunol.

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Traumatic brain injury (TBI) is a devastating condition due to its long-term sequelae on neurological functions. Inflammatory responses after TBI are critical for injury expansion and repair. Recent research in central nervous system (CNS) disorders reveals the importance of IL-33 and its receptor (ST2) as an alarmin system to initiate immune responses. This study explored the role of IL-33/ST2 signaling in TBI. TBI was induced in adult male C57BL/6J mice using a controlled cortical impact (CCI) model. We found that the expression of IL-33 increased in the injured brain and blood, and ST2 was elevated in the circulating and infiltrating regulatory T cells (Tregs) early after TBI. ST2 deficient mice exhibited reduced Treg numbers in the blood and brain 5 days after TBI. The brain lesion size was enlarged in ST2 knockout mice, which was accompanied by deteriorated sensorimotor function 5 days after TBI. In contrast, post-TBI treatment with IL-33 (2 μg/30 g body weight, intranasal) for 3 days significantly reduced brain lesion size and improved neurological functions 5 days after TBI. Meanwhile, IL-33 treatment increased ST2 expression in circulating and brain infiltrating Tregs. To further explore the involvement of Tregs in IL-33/ST2-mediated neuroprotection, Tregs were depleted by CD25 antibody injection. The absence of Tregs significantly reduced the protective effect of IL-33 after TBI. In vitro study confirmed that IL-33 (50 ng/ml) increased the production of IL-10 and TGFβ from activated Tregs and boosted the inhibitory effect of Tregs on T effector cell proliferation. Taken together, this study suggests that the activation of IL-33/ST2 signaling reduces brain lesion size and alleviates functional deficits after TBI at least partially through regulating the Treg response. IL-33 may represent a new immune therapeutic strategy to improve TBI outcomes.

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Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study

Cited by 11 publications

References 33 publications

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock

Tozorakimab (MEDI3506): a dual-pharmacology anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction

IL-33/ST2 Axis Protects Against Traumatic Brain Injury Through Enhancing the Function of Regulatory T Cells

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