Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury

Wicher, Grzegorz; Wallenquist, Ulrika; Lei, Ying; Enoksson, Mattias; Li, Xiaofei; Fuchs, Barbara; Hamdeh, Sami Abu; Marklund, Niklas; Hillered, Lars; Nilsson, Gunnar; Forsberg-Nilsson, Karin

doi:10.1089/neu.2016.4900

Cited by 48 publications

(46 citation statements)

References 34 publications

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“…We also saw a significant increases in the astrocyte activation marker S100a6 (1.7 fold), the cytokine Il6 (2.4 fold), and Il33 (1.6 fold) ( Fig. S2A), an astrocytic cytokine implicated in astrocyte-microglia signaling (Wicher et al, 2017). Thus, disruption of circadian function via knockdown of Bmal1 in WT astrocytes induces a cell-autonomous reactive phenotype in vitro.…”

Section: Resultsmentioning

confidence: 78%

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Lananna

Nadarajah

Izumo

et al. 2018

Preprint

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Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism, and via a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a novel mechanism by which the circadian clock could influence many aspects of brain function and neurologic disease. Highlights:• Circadian disruption promotes astrocyte activation.• Astrocyte-specific deletion of the circadian clock gene BMAL1 induces astrocyte activation. • BMAL1 regulates astrocyte activation by altering glutathione-s-transferase signaling.• Loss of astrocyte BMAL1 enhances neuronal cell death in a co-culture system. eTOC blurb:Lananna et al. show that the circadian clock protein BMAL1 regulates astrocyte activation via a cell autonomous-mechanism involving diminished glutathione-s-transferase signaling. This finding elucidates a novel function of the core circadian clock in astrocytes, and reveals a BMAL1 as a modulator of astrogliosis.

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Section: Resultsmentioning

confidence: 78%

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Lananna

Nadarajah

Izumo

et al. 2018

Preprint

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“…Bmal1 knockdown (KD) in astrocytes induced a highly consistent (across 14 independent experiments) 36% increase in Gfap mRNA expression (Figure S2A) as well as a 68% increase in GFAP protein (Figures 2C and 2D). We also saw significant increases in the astrocyte activation marker S100a6 (1.7-fold), the cytokine Il6 (2.4-fold), and Il33 (1.6-fold) (Figure S2A), an astrocytic cytokine implicated in astrocyte-microglia signaling (Wicher et al, 2017). Bmal1 KD in primary astrocytes from Per2 -luciferase reporter mice caused a loss of circadian Per2 rhythms (Figure 2E).…”

Section: Resultsmentioning

confidence: 90%

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

et al. 2018

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SUMMARY Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease.

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“…Mice lacking IL-33 had impaired recovery after CNS injury, which is associated with reduced myeloid cell infiltrates and decreased induction of M2 genes at the injury site [173]. Wicher et al (2017) used samples from human TBI microdialysate, tissue sections from human TBI, and mouse models of central nervous system injury and found that expression of IL-33 in the brain was elevated from nondetectable levels, reaching a maximum after 72 h in both human samples and mouse models [174]. The authors have shown that astrocytes and oligodendrocytes were the main producers of IL-33 [174].…”

Section: Interleukin-33mentioning

confidence: 99%

“…Wicher et al (2017) used samples from human TBI microdialysate, tissue sections from human TBI, and mouse models of central nervous system injury and found that expression of IL-33 in the brain was elevated from nondetectable levels, reaching a maximum after 72 h in both human samples and mouse models [174]. The authors have shown that astrocytes and oligodendrocytes were the main producers of IL-33 [174]. Post-TBI brains of mice deficient in the IL-33 receptor, ST2, contained fewer microglia/macrophages in the injured region as compared to the wild-type controls and had an altered cytokine/chemokine profile in response to injury [174].…”

Section: Interleukin-33mentioning

confidence: 99%

“…The authors have shown that astrocytes and oligodendrocytes were the main producers of IL-33 [174]. Post-TBI brains of mice deficient in the IL-33 receptor, ST2, contained fewer microglia/macrophages in the injured region as compared to the wild-type controls and had an altered cytokine/chemokine profile in response to injury [174]. Taken together, these observations indicate that IL-33 plays a role in neuroinflammation with microglia/ macrophages being cellular targets for this interleukin post-TBI.…”

Section: Interleukin-33mentioning

confidence: 99%

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Damage-associated molecular patterns in trauma

Relja

Land

2019

Eur J Trauma Emerg Surg

129

131

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In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

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Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury

Cited by 48 publications

References 34 publications

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

Damage-associated molecular patterns in trauma

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