Modulation of Post-Traumatic Immune Response Using the IL-1 Receptor Antagonist Anakinra for Improved Visual Outcomes

Evans, Lucy; Woll, Addison W.; Wu, Shu; Todd, Brittany P.; Hehr, N. N.; Hedberg-Buenz, Adam; Anderson, Michael G.; Newell, Elizabeth A.; Ferguson, Polly J.; Mahajan, Vinit B.; Harper, Matthew M.; Bassuk, Alexander G.

doi:10.1089/neu.2019.6725

Cited by 22 publications

(31 citation statements)

References 65 publications

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“…This is in contrast to the effect of IL-1RI pharmacological block with anakinra, which prevents both IL-1α and IL-1β cytokine signaling and protects mice from blast injury. 19 Nevertheless, the percent change between sham and blast groups in the number of surviving RGCs, RGC complex layer thickness, and RGC signaling was smaller for all three KO groups when compared to WT, suggesting that partial protection might be conferred by removal of these IL-1 pathway components and that these molecules may play a role in post-bTBI injury pathogenesis ( Tables 1 – 3 ). When comparing the blast cohorts, some KOs demonstrated significantly less damage than the WT mice, again suggesting that the loss of these molecules may provide partial protection from retinal injury after bTBI.…”

Section: Discussionmentioning

confidence: 96%

“…In recent experiments, the IL-1 pathway was pharmacologically blocked after bTBI to test whether acutely modulating this inflammatory IL-1 signaling might prevent subsequent neuronal deficits. 19 When the IL-1RI antagonist anakinra was used to block the acute inflammatory responses after bTBI, microglia and Müller glia activation was reduced. Additionally, anakinra reduced retinal neuroinflammation, which preserved optic nerve integrity, RGC function, and RGC layer thickness.…”

mentioning

confidence: 99%

“…Additionally, anakinra reduced retinal neuroinflammation, which preserved optic nerve integrity, RGC function, and RGC layer thickness. 19 Still, this pharmacologic intervention did not provide complete protection, leaving unanswered questions concerning the efficacy of anakinra, the particular IL-1 molecules driving the visual pathology, and how to more effectively target the neuroinflammation that drives retinal damage after bTBI.…”

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confidence: 99%

“…The complete deletion of IL-1 pathway components enabled this complementary study to parallel and compare the acute pharmacologic blockade of IL-1RI that was recently reported. 19 …”

mentioning

confidence: 99%

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Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Evans

Boehme

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose In a mouse model of blast-mediated traumatic brain injury (bTBI), interleukin-1 (IL-1)-pathway components were tested as potential therapeutic targets for bTBI-mediated retinal ganglion cell (RGC) dysfunction. Sex was also evaluated as a variable for RGC outcomes post-bTBI. Methods Male and female mice with null mutations in genes encoding IL-1α, IL-1β, or IL-1RI were compared to C57BL/6J wild-type (WT) mice after exposure to three 20-psi blast waves given at an interblast interval of 1 hour or to mice receiving sham injury. To determine if genetic blockade of IL-1α, IL-1β, or IL-1RI could prevent damage to RGCs, the function and structure of these cells were evaluated by pattern electroretinogram and optical coherence tomography, respectively, 5 weeks following blast or sham exposure. RGC survival was also quantitatively assessed via immunohistochemical staining of BRN3A at the completion of the study. Results Our results showed that male and female WT mice had a similar response to blast-induced retinal injury. Generally, constitutive deletion of IL-1α, IL-1β, or IL-1RI did not provide full protection from the effects of bTBI on visual outcomes; however, injured WT mice had significantly worse visual outcomes compared to the injured genetic knockout mice. Conclusions Sex does not affect RGC outcomes after bTBI. The genetic studies suggest that deletion of these IL-1 pathway components confers some protection, but global deletion from birth did not result in a complete rescue.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…The complete deletion of IL-1 pathway components enabled this complementary study to parallel and compare the acute pharmacologic blockade of IL-1RI that was recently reported. 19 …”

mentioning

confidence: 99%

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Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Evans

Boehme

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…A study in canine showed that blast exposure activated NF-κB and MAPK signaling pathways in lung tissues and triggered nuclear translocations of NF-κB, which in turn regulated the transcription of downstream genes, such as IL-6 and TNF-α [25]. In a phase 2 clinical trial, the use of anti-IL-1β antibody or blocking IL-1R expression signi cantly reduced the in ammatory response caused by blast exposure and signi cantly improved the symptoms of patients with severe blast injuries [26]. The lung began to exhibit early in ammatory after 3 h of blast exposure, followed by epithelial cell damage after 12 h of blast exposure, and the in ammation and oxidation reached the peak at 24 h and 48 h [27].…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis and identification of differentially expressed proteins involved in blast exposure-induced inflammatory response

Liu¹,

Tong

Cong

et al. 2020

Preprint

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Abstract Background Previous studies found that blast injury caused a significant increased expression of interleukin-1, IL-6 and tumor necrosis factor, a significant decrease in the expression of IL-10, an increase in Evans blue leakage, and a significant increase in inflammatory cell infiltration in the lungs. However, the molecular characteristics of lung injury at different time points after blast exposure have not yet been reported. Therefore, in this study, tandem mass spectrometry (TMT) quantitative proteomics and bioinformatics analysis were used for the first time to gain a deeper understanding of the molecular mechanism of lung blast injury at different time points. Methods Fourty-eight male C57BL/6 mice were randomly divided into six groups: control, 12 h, 24 h, 48 h, 72 h and 1 w after low-intensity blast exposure. TMT quantitative proteomics and bioinformatics analysis were performed to analyze protein expression profiling in the lungs from control and blast-exposed mice, and differential protein expression was verified by Western blotting. Results The results demonstrated that blast exposure induced severe lung injury, leukocyte infiltration, and the production of inflammatory factors in mice. After analyzing the expression changes in global proteins and inflammation-related proteomes after blast exposure, the results showed that a total of 6,861 global proteins and 608 differentially expressed proteins were identified, of which 215, 128, 187, 232, and 65 proteins were identified at 12 h, 24 h, 48 h, 72 h, and 1 week after blast exposure, respectively. Moreover, blast exposure-induced 177 differentially expressed proteins were associated with inflammatory responses, which were enriched in the inflammatory response regulation, leukocyte transendothelial migration, phagocytosis, and immune response. Conclusions Therefore, blast exposure may induce early inflammatory response of lung tissue by regulating the expression of key proteins in the inflammatory process, suggesting that early inflammatory response may be the initiating factor of lung blast injury. These data can provide potential therapeutic candidates or approaches for the development of future treatment of lung blast injury.

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Research Progress on the Immune-Inflammatory Mechanisms of Posttraumatic Epilepsy

Dang,

Wang

2023

Cell Mol Neurobiol

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Modulation of Post-Traumatic Immune Response Using the IL-1 Receptor Antagonist Anakinra for Improved Visual Outcomes

Cited by 22 publications

References 65 publications

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Quantitative proteomic analysis and identification of differentially expressed proteins involved in blast exposure-induced inflammatory response

Research Progress on the Immune-Inflammatory Mechanisms of Posttraumatic Epilepsy

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