Interleukin-13 Propagates Prothrombin Kringle-2-Induced Neurotoxicity in Hippocampi In Vivo via Oxidative Stress

Jeong, Jae Yeong; Wi, Rayul; Chung, Young Cheul; Jin, Byung Kwan

doi:10.3390/ijms22073486

Cited by 5 publications

(14 citation statements)

References 54 publications

(49 reference statements)

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“…In the present study, we demonstrated that IL-13 originated from reactive microglia/macrophage mediates destruction of BBB and loss of astrocytes, leading to neurodegeneration in LPS-injected striatum in vivo. This finding is in line with our reports showing that IL-13 contributes to the production of proinflammatory cytokines and/or oxidative stress, leading to neurodegeneration in thrombin- [34], Aβ 1-42 - [20] or pKr-2-injected hippocampus in vivo [4]. It is therefore likely that these apparent discrepancies may be attributed to the use of different stimuli (LPS vs thrombin, Aβ 1-42 or pKr-2) and/or target areas (striatum vs cortex or hippocampus) although the underlying mechanisms remain to be determined.…”

Section: Discussionsupporting

confidence: 93%

Interleukin 13 on Microglia is Neurotoxic in Lipopolysaccharide-injected Striatumin vivo

et al. 2022

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To explore the potential function of interleukin-13 (IL-13), lipopolysaccharide (LPS) or PBS as a control was unilaterally microinjected into striatum of rat brain. Seven days after LPS injection, there was a significant loss of neurons and microglial activation in the striatum, visualized by immunohistochemical staining against neuronal nuclei (NeuN) and the OX-42 (complement receptor type 3, CR3), respectively. In parallel, IL-13 immunoreactivity was increased as early as 3 days and sustained up to 7 days post LPS injection, compared to PBS-injected control and detected exclusively within microglia. Moreover, GFAP immunostaining and blood brain barrier (BBB) permeability evaluation showed the loss of astrocytes and disruption of BBB, respectively. By contrast, treatment with IL-13 neutralizing antibody (IL-13NA) protects NeuN + neurons against LPSinduced neurotoxicity in vivo. Accompanying neuroprotection, IL-13NA reduced loss of GFAP + astrocytes and damage of BBB in LPS-injected striatum. Intriguingly, treatment with IL-13NA produced neurotrophic factors (NTFs) on survived astrocytes in LPS-injected rat striatum. Taken together, the present study suggests that LPS induces expression of IL-13 on microglia, which contributes to neurodegeneration via damage on astrocytes and BBB disruption in the striatum in vivo.

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Section: Discussionsupporting

confidence: 93%

Interleukin 13 on Microglia is Neurotoxic in Lipopolysaccharide-injected Striatumin vivo

et al. 2022

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“…To determine activation of microglia in the stratum by LPS in vivo, sections adjacent to those used for NeuN immunostaining were processed for immunohistochemical staining using antibodies against OX-42 and OX-6 to detect microglial activation, as recently described [ 31 ]. In the PBS-injected striatum, OX-42 + cells exhibited the resting state with small cell bodies and ramified processes ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…Brains were removed from the skulls, postfixed overnight in buffered 4% paraformaldehyde at 4 °C, stored in a 30% sucrose solution for 24–48 h at 4 °C until they sank, and were frozen-sectioned on a sliding microtome in 40-µm-thick coronal sections. All sections were collected in six separate series and processed for immunohistochemical staining, as described previously [ 31 ]. In brief, brain sections were rinsed in PBS and then incubated overnight at room temperature with the following primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…For immunofluorescence double labeling, tissue sections were processed as described previously [ 31 ]. Briefly, 40-um-thick coronal sections were mounted on gelatin-coated slides, derided for 20 min at room temperature, rinsed in PBS, and incubated overnight at room temperature with primary antibodies, as used above.…”

Section: Methodsmentioning

confidence: 99%

“…As described [ 31 ], imaging data were analyzed in Image J (National Institutes of Health, USA) to quantify the expression of IL-4, nitrotyrosine, 8-OHdG, iNOS, and Arg1 in the LPS-injected striatum. Immunofluorescence was quantified by Image J with the colocalization plugin.…”

Section: Methodsmentioning

confidence: 99%

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Interleukin-4 Aggravates LPS-Induced Striatal Neurodegeneration In Vivo via Oxidative Stress and Polarization of Microglia/Macrophages

Jang

Hong

Chung

et al. 2022

IJMS

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The present study investigated the effects of interleukin (IL)-4 on striatal neurons in lipopolysaccharide (LPS)-injected rat striatum in vivo. Either LPS or PBS as a control was unilaterally injected into the striatum, and brain tissues were processed for immunohistochemical and Nissl staining or for hydroethidine histochemistry at the indicated time points after LPS injection. Analysis by NeuN and Nissl immunohistochemical staining showed a significant loss of striatal neurons at 1, 3, and 7 days post LPS. In parallel, IL-4 immunoreactivity was upregulated as early as 1 day, reached a peak at 3 days, and was sustained up to 7 days post LPS. Increased levels of IL-4 immunoreactivity were exclusively detected in microglia/macrophages, but not in neurons nor astrocytes. The neutralizing antibody (NA) for IL-4 significantly protects striatal neurons against LPS-induced neurotoxicity in vivo. Accompanying neuroprotection, IL-4NA inhibited activation of microglia/macrophages, production of reactive oxygen species (ROS), ROS-derived oxidative damage and nitrosative stress, and produced polarization of microglia/macrophages shifted from M1 to M2. These results suggest that endogenous IL-4 expressed in LPS-activated microglia/macrophages contributes to striatal neurodegeneration in which oxidative/nitrosative stress and M1/M2 polarization are implicated.

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Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

et al. 2022

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Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.

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Interleukin-13 Propagates Prothrombin Kringle-2-Induced Neurotoxicity in Hippocampi In Vivo via Oxidative Stress

Cited by 5 publications

References 54 publications

Interleukin 13 on Microglia is Neurotoxic in Lipopolysaccharide-injected Striatumin vivo

Interleukin 13 on Microglia is Neurotoxic in Lipopolysaccharide-injected Striatumin vivo

Interleukin-4 Aggravates LPS-Induced Striatal Neurodegeneration In Vivo via Oxidative Stress and Polarization of Microglia/Macrophages

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

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