Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma

Sun, Mujun; Brady, Rhys D.; Wright, David K.; Kim, Hyun Ah; Zhang, Shenpeng R.; Sobey, Christopher G.; Johnstone, Maddison R; O’Brien, Terence J.; Semple, Bridgette D.; McDonald, Stuart J.; Shultz, Sandy R.

doi:10.1016/j.bbi.2017.08.005

Cited by 68 publications

(50 citation statements)

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“…Intriguingly, IL-1ra, a natural inhibitor of IL-1, was evidently higher in the hAEC-CM compared to that of hEF-CM, indicating its crucial role in suppressing inflammation response. In support of our hypothesis, a recent study reported that IL-1ra attenuates the traumatic brain injury mice and decreases the activated microglia cells and astrocytes contributing to the reduction of neuroinflammatory response [45]. Additionally, Sachiko Tanaka found that LPS induces microglial activation and PD-like behavior impairment in both wild-type and TNFα KO mice, but not IL-1 KO mice.…”

Section: Discussionsupporting

confidence: 83%

Human Amniotic Epithelial Cells Recover Mouse model of Parkinson’s Disease mainly by Neuroprotective，Anti-oxidative and Anti-inflammatory factors

Zhang

Yang

et al. 2020

Preprint

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Objectives: Human amniotic epithelial cells (hAECs) have been reported to have neuroprotective roles in neurological diseases including Parkinson’s Disease (PD) in animal models. However, the mechanism is not fully understood.Materials and method : Firstly, hAECs were transplanted into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP )-induced PD mice. And the motor deficits were tested by Rotarod test. Secondly, injury severity of nigral dopaminergic neurons in substantia nigra and striatal axon fibers in PD mice was estimated by immunochemistry with tyrosine hydroxylase antibody. Thirdly, neuroinflammation was measured by microglial activation and the level of inflammatory factor levels. Lastly, the oxidative stress was tested by the level of reactive oxidative species (ROS) levels. In vitro, we examined a full spectrum of soluble proteins of hAECs by Raybiotech human Antibody Array 507. Besides, antibody neutralization experiments were used to determine the role of many factors on dopaminergic neurons.Results: hAECs significantly attenuated the motor deficits of PD mice. Moreover, the grafts prevented the loss of nigral dopaminergic neurons, promoted the outgrowth of their neurites and striatal axon fibers in PD mice. More importantly, decreased microglial activation, inflammatory factor levels and MPTP-induced excessive ROS levels were also observed in hAEC-treated PD mice. In vitro, analysis of an antibody array of 507 soluble target proteins using hAEC-CM revealed that the levels of many neurotrophic factors, growth factors， neuronal cell adhesion molecule ( NrCAM )，and anti-inflammatory factors were evidently high. In addition, antibody neutralization experiments showed that many of them contributed to the survival and growth of dopaminergic neurons and the outgrowth of their neurites.Conclusion: Our study indicates that the neuroprotection effects by hAECs grafts are achieved not only by neuroprotection and neurite outgrowth-promoting activities, but also by anti-inflammation and anti-oxidation functions in the microenvironment of the damaged dopaminergic neurons, so to facilitate the restoration of neurological functions.

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Section: Discussionsupporting

confidence: 83%

Human Amniotic Epithelial Cells Recover Mouse model of Parkinson’s Disease mainly by Neuroprotective，Anti-oxidative and Anti-inflammatory factors

Zhang

Yang

et al. 2020

Preprint

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“…As expected, our results indicated that the ipsilateral hemisphere of TBI mice contained significantly increased total leukocytes, myeloid cells, T cells, neutrophils and monocytes when compared to sham-operated mice at 48 h post-injury. These findings add to the growing literature suggesting a significant infiltration of immune cells during the acute stages of TBI [30,[34][35][36][37]. However, treatment with hAECs was not sufficient to prevent such infiltration.…”

Section: Discussionsupporting

confidence: 57%

Systemic treatment with human amnion epithelial cells after experimental traumatic brain injury

Kim

Semple

Dill

et al. 2020

Preprint

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Background: Systemic administration of human amnion epithelial cells (hAECs) was recently shown to reduce neuropathology and improve functional recovery following ischemic stroke in both mice and marmosets. Given the significant neuropathological overlap between ischemic stroke and traumatic brain injury (TBI), we hypothesized that a similar hAEC treatment regime would also improve TBI outcomes. Methods: Male mice (12 weeks old, n=40) were given a sham injury or moderate severity TBI by controlled cortical impact. At 60 minutes post-injury, mice were given a single tail vein injection of either saline (vehicle) or 1x10 6 hAECs suspended in saline. At 24 h post-injury, mice were assessed for locomotion and anxiety using an open field, and sensorimotor ability using a rotarod. At 48 h post-injury, brains were collected for analysis of immune cells via flow cytometry, or histological evaluation of lesion volume and hAEC penetration. To assess the impact of TBI and hAECs on lymphoid organs, spleen and thymus weights were determined. Results: Treatment with hAECs did not prevent TBI-induced sensorimotor deficits at 24 h post-injury. hAECs were detected in the injured brain parenchyma; however, lesion volume was not altered by hAEC treatment. Robust increases in several leukocyte populations in the ipsilateral hemisphere of TBI mice were found when compared to sham mice at 48 h post-injury; however, hAEC treatment did not alter brain immune cell numbers.Both TBI and hAEC treatment were found to increase spleen weight. Conclusions: Taken together, these findings indicate that -unlike in ischemic stroke -treatment with hAEC was unable to prevent immune cell infiltration and sensorimotor deficits in the acute stages following controlled cortical impact in mice. Although further investigations are required, our data suggests that the lack of hAECinduced neuroprotection in the current study may be explained by the differential splenic contributions to neuropathology between these brain injury models. Background Traumatic brain injury (TBI) is a leading causing of death and disability worldwide [1, 2]. Although numerous treatments have proved promising in rodent models of experimental TBI, all pharmacological agents investigated to date have failed to improve outcomes in clinical trials [3-6]. The diverse nature of clinical TBI is likely to be a major contributor to such failures, with individual Declarations Ethics approval and consent to participate: All procedures were approved by the Animal Ethics Committee at La Trobe University (AEC #18-032). Authors' contributions: HK, BDS, CGS and SJM conceptualized the study. HK, BDS, LP and SJM conducted animal surgeries. RL isolated and quantified hAECs. SJM and LP conducted behavioral testing. LKD, SD, SZ and BDS conducted histology. HK conducted flow cytometry. All authors contributed to data interpretation, manuscript preparation and finalization. Acknowledgments: traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease St...

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“…Initial clinical trials have provided evidence that IL-1Ra treatment results in an increase of pro-inflammatory M1type macrophages, characterized by increased GM-CSF and IL-1β cytokine levels, whereas levels of IL-4, IL-10, and MDC -the cytokines associated with anti-inflammatory M2type macrophages -are reduced (Helmy et al, 2016). These results counter previous studies showing decreases in IL-1β levels in treated groups (Sun et al, 2017). The classical view is that M1-differentiated cells induce pro-inflammatory responses and M2 macrophages antagonize pro-inflammatory responses (Martinez and Gordon, 2014); however, this view has recently come under increased scrutiny as microglia and/or macrophages exhibit a wide range of phenotypes that may be induced through a variety of insults.…”

Section: Il-1ramentioning

confidence: 78%

“…Polytrauma-induced increases in IL-1β are time dependent however as after 48 h the levels of IL-1β decrease compared to TBI-only controls (Maegele et al, 2007). Sustained inhibition of polytrauma-elicited increases in IL-1 signaling using IL-1Ra reduces cortical neutrophil infiltration, cerebral edema, and brain atrophy following a CHI weight-drop model with concomitant tibial fracture (Sun et al, 2017). It should be noted, however, that IL-1R1 administration did not mitigate behavioral deficits in the MWM, Crawley three-chamber sociability task, open field, or rotarod test (Sun et al, 2017).…”

Section: Il-1ramentioning

confidence: 97%

Contributions of Interleukin-1 Receptor Signaling in Traumatic Brain Injury

Thome

Reeder

Collins

et al. 2020

Front. Behav. Neurosci.

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Traumatic brain injury (TBI) in various forms affects millions in the United States annually. There are currently no FDA-approved therapies for acute injury or the chronic comorbidities associated with TBI. Acute phases of TBI are characterized by profound neuroinflammation, a process that stimulates the generation and release of proinflammatory cytokines including interleukin-1α (IL-1α) and IL-1β. Both forms of IL-1 initiate signaling by binding with IL-1 receptor type 1 (IL-1R1), a receptor with a natural, endogenous antagonist dubbed IL-1 receptor antagonist (IL-1Ra). The recombinant form of IL-1Ra has gained FDA approval for inflammatory conditions such as rheumatoid arthritis, prompting interest in repurposing these pharmacotherapies for other inflammatory diseases/injury states including TBI. This review summarizes the currently available preclinical and clinical literature regarding the therapeutic potential of inhibiting IL-1-mediated signaling in the context of TBI. Additionally, we propose specific research areas that would provide a greater understanding of the role of IL-1 signaling in TBI and how these data may be beneficial for the development of IL-1-targeted therapies, ushering in the first FDA-approved pharmacotherapy for acute TBI.

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Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma

Cited by 68 publications

References 51 publications

Human Amniotic Epithelial Cells Recover Mouse model of Parkinson’s Disease mainly by Neuroprotective，Anti-oxidative and Anti-inflammatory factors

Human Amniotic Epithelial Cells Recover Mouse model of Parkinson’s Disease mainly by Neuroprotective，Anti-oxidative and Anti-inflammatory factors

Systemic treatment with human amnion epithelial cells after experimental traumatic brain injury

Contributions of Interleukin-1 Receptor Signaling in Traumatic Brain Injury

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