Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury

Helmy, Adel; Guilfoyle, Mathew R.; Carpenter, Keri L.H.; Pickard, John D.; Menon, David; Hutchinson, Peter J.

doi:10.1177/0271678x15620204

Cited by 73 publications

(83 citation statements)

References 44 publications

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“…The innate immune system is a key player in the detrimental secondary injury cascades following TBI (93), and this provides the rationale as to why it would be beneficial to target pro-inflammatory interleukin-1 activity. All patients were monitored using MD, and not only were the authors able to accurately study the pharmacokinetics in the brain ECF of the subcutaneously administered drug, they also noted the changes of downstream chemokines and cytokines in the treated group vs placebo, extracted from the brain ECF as well (26,94). Similarly, another randomized control trial analysing antipterin VAS203 (a nitric oxide synthase inhibitor) in TBI noted increased metabolites of the drug in the brain, extracted using MD, in the treatment group as compared to those in placebo (95).…”

Section: Pharmacokinetics Of Neuroprotective Agentsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

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Abstract.Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

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Section: Pharmacokinetics Of Neuroprotective Agentsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

Self Cite

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“…Although some studies demonstrate promising therapeutic effects on TBI through eliminating single cytokine or chemokine (CXCL1, CXCL2, CCL2, IL1, TNF-α) [11,12,44,46], it may be advantageous to target at the multiple factors. Here, we observed extensive decreases of pro-inflammatory cytokines and chemokines, but an increase of anti-inflammatory cytokine after fingolimod treatment on the 3rd day after TBI.…”

Section: Cd25-pementioning

confidence: 99%

“…However, recent studies demonstrate that CD4+ T lymphocyte protected injured neurons [9]. Although a large number of anti-inflammatory drugs including nonsteroidal antiinflammatory drugs (NSAIDS) [10], TNF-α inhibitors [11], IL-1 inhibitors [12], and corticosteroids [13] have been tested in both preclinical and clinical experiments, but few efficient treatments have been developed [14]. Therefore, the immunoinflammatory responses after TBI and how to modulate them appropriately require further investigations.…”

Section: Introductionmentioning

confidence: 99%

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Gao

Huang

et al. 2016

Mol Neurobiol

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Excessive inflammation after traumatic brain injury (TBI) is a major cause of secondary TBI. Though several inflammatory biomarkers have been postulated as the risk factors of TBI, there has not been any comprehensive description of them. Fingolimod, a new kind of immunomodulatory agent which can diminish various kinds of inflammatory responses, has shown additional therapeutic effects in the treatment of intracranial cerebral hematoma (ICH), ischemia, spinal cord injury (SCI), and many other CNS disorders. However, its therapeutic application has not been confirmed in TBI. Thus, we hypothesized that a 3-day consecutive fingolimod administration could broadly modulate the inflammatory reactions and improve the outcomes of TBI. The TBI models of C57/BL6 mice were established with the controlled cortical impact injury (CCI) system. A 3-day consecutive fingolimod therapy (given at 1, 24, and 48 h post injury) was performed at a dose of 1 mg/kg. The flow cytometry, immunoflourence, cytokine array, and ELISA were all applied to evaluate the immune cells and inflammatory markers in the injured brains. Immunohistochemical staining with anti-APP antibody was performed to assess the axonal damage. The neurological functions of these TBI models were assessed by mNSS/Rota-rod and Morris water maze (MWM). The brain water content and integrity of the blood-brain barrier (BBB) were also observed. On the 3rd day after TBI, the accumulation of inflammatory cytokines and chemokines reached the peak and administration of fingolimod reduced as many as 20 kinds of cytokines and chemokines. Fingolimod decreased infiltrated T lymphocytes and NK cells but increased the percentage of regulatory T (Treg) cells, and the concentration of IL-10 on the 3rd day after TBI. Fingolimod also notably attenuated the general activated microglia but augmented the M2/M1 ratio accompanied by decreased axonal damage. The neurological functions were improved after the fingolimod treatment accompanied with alleviation of the brain edema and BBB damage. This study suggests that the 3-day consecutive fingolimod administration extensively modulates multiple immuno-inflammatory responses and improves the neurological deficits after TBI, and therefore, it may be a new approach to the treatment of secondary TBI.

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“…A phase II clinical trial examining the use of subcutaneous IL-1R antagonist, anakinra, initially administered within 6 h post-stroke with repeat dosing every 12 h for a total of 6 injections over 72 h (ISRCTN74236229) has recently been completed. In TBI, as previously stated, Helmy et al showed the safety of IL-1R antagonists, but actually reported an increase in the pro-inlammatory M1 microglia phenotype, acknowledging the variation in the immune response depending on the mechanism of injury [109]. The of-label perispinal administration of the anti-TNF-α monoclonal antibody, etanercept in post-stroke cognitive dysfunction and TBI have demonstrated beneit as well [245].…”

Section: Biological Response Modiiers In Tbi and Aismentioning

confidence: 85%

“…However, in a study examining the use of the recombinant human IL-1Ra (i.e, anakinra), in patients with severe TBI, treatment, while safe without serious adverse efects, was found to induce a shift in cytokine levels towards an unexpected phenotypically M1 microglial response in comparison to non-treated controls [109,110]. These indings evidence a more broadly deined role for IL-1Ra in TBI and the efect of IL-1Ra on microglial activation.…”

Section: Inlammatory Il-1β In Tbimentioning

confidence: 96%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury

Cited by 73 publications

References 44 publications

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

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