Critical Roles of IL-33/ST2 Pathway in Neurological Disorders

Isnadi, Mohammad Faruq Abd Rachman; Chin, Voon Kin; Majid, Roslaini Abd; Lee, Tze Yan; Abdullah, Maizaton Atmadini; Omenesa, Ramatu Bello; Ibraheem, Zaid O.; Basir, Rusliza

doi:10.1155/2018/5346413

Cited by 23 publications

(23 citation statements)

References 89 publications

(141 reference statements)

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“…Mouse mast cell proteases MMCP-6 and MMCP-7 upregulate PAR-2 expression in glia, neurons and mast cells [78]. Mast cells are implicated in neuroinflammation and AD in association with the detection of IL-33 [52]. Our present study also show similar results that IL-33 and mast cells are increased in PD brains.…”

Section: Discussionsupporting

confidence: 89%

“…Immune system detects CNS injury and responds rapidly and this response may be beneficial or detrimental in association with M2 (neurotoxic) and M1 (neuroprotective) microglia phenotypes. IL-33 exhibits both pro and anti-inflammatory properties as double-edged sword based upon the site and disease conditions [52]. Alarmin cytokine, IL-33 released from injured cells in the CNS acts on local microglia and astrocytes to release chemokine to attract immune cells into the site of injury to prevent further injury and inflammatory processes [53].…”

Section: Discussionmentioning

confidence: 99%

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Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-κB

et al. 2018

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Inflammatory mediators released from activated microglia, astrocytes, neurons, and mast cells mediate neuroinflammation. Parkinson's disease (PD) is characterized by inflammation-dependent dopaminergic neurodegeneration in substantia nigra. 1-Methyl-4-phenylpyridinium (MPP), a metabolite of parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), induces inflammatory mediators' release from brain cells and mast cells. Brain cells' interaction with mast cells is implicated in neuroinflammation. However, the exact mechanisms involved are not yet clearly understood. Mouse fetal brain-derived cultured primary astrocytes and glia-neurons were incubated with mouse mast cell protease-6 (MMCP-6) and MMCP-7, and mouse bone marrow-derived mast cells (BMMCs) were incubated with MPP and brain protein glia maturation factor (GMF). Interleukin-33 (IL-33) released from these cells was quantitated by enzyme-linked immunosorbent assay. Both MMCP-6 and MMCP-7 induced IL-33 release from astrocytes and glia-neurons. MPP and GMF were used as a positive control-induced IL-33 and reactive oxygen species expression in mast cells. Mast cell proteases and MPP activate p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), mitogen-activated protein kinases (MAPKs), and transcription factor nuclear factor-kappa B (NF-κB) in astrocytes, glia-neurons, or mast cells. Addition of BMMCs from wt mice and transduction with adeno-GMF show higher chemokine (C-C motif) ligand 2 (CCL2) release. MPP activated glial cells and reduced microtubule-associated protein 2 (MAP-2) expression indicating neurodegeneration. IL-33 expression increased in the midbrain and striatum of PD brains as compared with age- and sex-matched control subjects. Glial cells and neurons interact with mast cells and accelerate neuroinflammation and these interactions can be explored as a new therapeutic target to treat PD.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-κB

et al. 2018

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“…The study further reviews that apigenin and luteolin suppressed the production of IL-31 and IL-33 by inhibiting their gene and protein expressions in the microglia cells, and finally inhibiting their secretion out of the microglial cells. The ability of apigenin and luteolin to regulate LPS-induced microglia activation and subsequent pro-inflammatory IL-31 and IL-33 mediators may be useful in the treatment of inflammatory diseases in the CNS including Alzheimer's disease, malaria infections, itch caused by the release of itch mediator within the CNS, and autoimmune diseases like multiple sclerosis, where there is a positive correlation with IL-31 or IL-33 [6,[25][26][27]. The data adds more knowledge to the current understanding of the anti-inflammatory activities of these two flavonoids that have also been previously reported to be neuroprotective by modulating other inflammatory mediators [17,[28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Effect of Luteolin and Apigenin on the Production of Il-31 and Il-33 in Lipopolysaccharides-Activated Microglia Cells and Their Mechanism of Action

et al. 2020

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Microglia cells are resident cells of the central nervous system (CNS) charged with modulating inflammation in the CNS. Overstimulation of microglia cells continuously releases inflammatory mediators that contribute to neurodegenerative diseases. Apigenin and Luteolin are flavonoids with reported anti-inflammatory activities. However, their effects on IL-31 and IL-33 production in microglial cells are unknown. Here, we investigated the effects of apigenin and luteolin on the production of IL-31 and IL-33 by microglia cells. SIM-A9 microglial cells were pre-treated with apigenin or luteolin and stimulated with lipopolysaccharides to evaluate the production of IL-31 and IL-33. The study revealed that apigenin and luteolin inhibited the production of IL-31 and IL-33 at the gene and protein expressions and the secretion levels. Using potent inhibitors of MAPK, NF-κB, and STAT3 signaling pathways, we demonstrated that apigenin and luteolin's suppression of ERK and JNK contributed to the inhibition of IL-31 and IL-33 in the MAPK pathway. Luteolin's suppression of NF-κB and STAT3 also contributed to the inhibition of IL-31 and IL-33. Further analysis revealed that both compounds prevented nuclear translocation of activated NF-κB and STAT3, an act that subsequently prevented their DNA binding activities. Collectively, the study suggested that apigenin and luteolin's regulation of signaling pathways contributed to the inhibition of IL-31 and IL-33, thus suggesting its importance for the improvement of neurodegenerative diseases involving these two cytokines.

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“…Recently, IL-33 has also been involved in the pathogenesis of central nervous system (CNS) diseases such as neurodegenerative diseases, stroke, or infectious diseases. Broadly and highly expressed in the CNS in physiological conditions, IL-33 is described as a key regulator of neuroinflammation [ 2 – 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments

Reverchon

Concini

Larrigaldie

et al. 2020

J Neuroinflammation

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Background Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms. Methods We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ deficient mice. Chronic minocycline administration was performed and cognitive functions were examined trough spatial habituation test. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and fluorescence-activated cell sorting (FACS). Results We showed that IL-33 administration in mice led to a spatial memory performance defect associated with an increase of inflammatory markers in the hippocampus while minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ demonstrated an increase of proximal intersections per radius in each part of the hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting analysis on isolated microglia, revealed overexpression of IL-1β, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1αβ deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection. Conclusion Thus, hippocampal IL-33 induced an inflammatory state, including IL-1β overexpression by microglia cells, being causative of the cognitive impairment. These results highlight the pathological role for IL-33 in the central nervous system, independently of a specific neuropathological model.

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Critical Roles of IL-33/ST2 Pathway in Neurological Disorders

Cited by 23 publications

References 89 publications

Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-κB

Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-κB

Effect of Luteolin and Apigenin on the Production of Il-31 and Il-33 in Lipopolysaccharides-Activated Microglia Cells and Their Mechanism of Action

Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments

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