Forebrain specific heparin-binding epidermal growth factor-like growth factor knockout mice show exacerbated ischemia and reperfusion injury

Oyagi, Atsushi; Morimoto, Nobutaka; Hamanaka, Junya; Ishiguro, Mitsunori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

doi:10.1016/j.neuroscience.2011.04.034

Cited by 24 publications

(23 citation statements)

References 44 publications

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“…32,33 In fact, postischemic administration of HB-EGF protects against focal cerebral ischemia in the rat, 49 while Hb-egf KO mice exhibit exacerbated ischemia and reperfusion injury in the brain. 50 On the other hand, intravitreal injection of EGF does not exert protective effects against light-induced photoreceptor degeneration, 19 even though HB-EGF binds to and activates the EGF receptor (EGF receptor/ErbB1), 20 as does EGF. These differences indicate that other receptors may be associated with the protective effects of HB-EGF.…”

Section: Discussionmentioning

confidence: 99%

Role of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Light-Induced Photoreceptor Degeneration in Mouse Retina

Inoue

Tsuruma²,

Nakanishi³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Inoue Y, Tsuruma K, Nakanishi T, et al. Role of heparin-binding epidermal growth factor-like growth factor in light-induced photoreceptor degeneration in mouse retina. Invest Ophthalmol Vis Sci. 2013;54:3815-3829. DOI:10.1167/iovs.12-11236 PURPOSE. Although heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been reported to have protective effects against various neuronal cell damage, its role in the retina has not been elucidated. Here, we investigated its role in light-induced photoreceptor degeneration using retinas and ventral forebrain-specific Hb-egf knockout (KO) mice.METHODS. Disruption of Hb-egf was confirmed by b-galactosidase (LacZ) staining and RT-PCR. Time-dependent changes in retinal HB-EGF were measured using quantitative RT-PCR and Western blotting. Retinal damage was induced by exposure to light. Recombinant human HB-EGF was injected intravitreally. Electroretinogram (ERG) and histological analyses were performed. To evaluate the effect of HB-EGF against light irradiation-induced cell death, 661W cells, a transformed mouse cone cell line, were used. RESULTS.LacZ-positive cells were observed and Hb-egf deletion was confirmed in the retinas of Hb-egf KO mice. Hb-egf and pro-HB-EGF levels were increased after light exposure in wildtype (WT) mice. Exposure to light reduced the a-and b-wave amplitudes of the dark-adapted ERG, and also outer nuclear layer (ONL) thickness, in Hb-egf KO mice versus WT mice. Treatment with HB-EGF improved both the a-and b-wave amplitudes and the thickness of the ONL. The 661W cell death induced by light irradiation was exacerbated by Hb-egf knockdown. HB-EGF also protected against light-induced cell death and reduced reactive oxygen species (ROS) production in 661W cells. HB-EGF treatment improved the a-wave amplitudes and the thickness of the ONL in Hb-egf KO mice.CONCLUSIONS. These data suggest that HB-EGF plays a pivotal role in light-induced photoreceptor degeneration. It therefore warrants investigation as a potential therapeutic target for such light-induced retinal diseases as age-related macular degeneration.

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Section: Discussionmentioning

confidence: 99%

Role of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Light-Induced Photoreceptor Degeneration in Mouse Retina

Inoue

Tsuruma²,

Nakanishi³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Although it is possible that other EGFR ligands could be also involved in sPLA 2 -IIA-induced EGFR transactivation, the fact that the presence of a HB-EGF-neutralizing Ab prevented the molecular and biological effects of the phospholipase suggests that HB-EGF plays a major role in the response induced by the sPLA 2 -IIA. We focused mainly on HB-EGF because of the extensive literature showing its role in cell survival and proliferation, both in vivo and in vitro [58-61]. Whether the remnant C-terminal fragment generated, HB-EGF-CTF, translocates to the nucleus and plays any role in sPLA 2 -IIA signaling should be investigated in greater detail in the future.…”

Section: Discussionmentioning

confidence: 99%

Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

Martín

Cordova

Nieto

2012

J Neuroinflammation

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Background Activation of microglia, the primary component of the innate immune response in the brain, is a hallmark of neuroinflammation in neurodegenerative disorders, including Alzheimer’s disease (AD) and other pathological conditions such as stroke or CNS infection. In response to a variety of insults, microglial cells produce high levels of inflammatory cytokines that are often involved in neuronal injury, and play an important role in the recognition, engulfment, and clearance of apoptotic cells and/or invading microbes. Secreted phospholipase A 2 -IIA (sPLA 2 -IIA), an enzyme that interacts with cells involved in the systemic immune/inflammatory response, has been found up-regulated in the cerebrospinal fluid and brain of AD patients. However, despite several approaches, its functions in mediating CNS inflammation remain unknown. In the present study, the role of sPLA 2 -IIA was examined by investigating its direct effects on microglial cells. Methods Primary and immortalized microglial cells were stimulated by sPLA 2 -IIA in order to characterize the cytokine-like actions of the phospholipase. The hallmarks of activated microglia analyzed include: mitogenic response, phagocytic capabilities and induction of inflammatory mediators. In addition, we studied several of the potential molecular mechanisms involved in those events. Results The direct exposure of microglial cells to sPLA 2 -IIA stimulated, in a time- and dose-dependent manner, their phagocytic and proliferative capabilities. sPLA 2 -IIA also triggered the synthesis of the inflammatory proteins COX-2 and TNFα. In addition, EGFR phosphorylation and shedding of the membrane-anchored heparin-binding EGF-like growth factor (pro-HB-EGF) ectodomain, as well as a rapid activation/phosphorylation of the classical survival proteins ERK, P70S6K and rS6 were induced upon sPLA 2 -IIA treatment. We further demonstrated that the presence of an EGFR inhibitor (AG1478), a matrix metalloproteinase inhibitor (GM6001), an ADAM inhibitor (TAPI-1), and a HB-EGF neutralizing antibody abrogated the phenotype of activated microglia induced by the sPLA 2 -IIA. Conclusion These results support the hypothesis that sPLA 2 -IIA may act as a potent modulator of microglial functions through its ability to induce EGFR transactivation and HB-EGF release. Accordingly, pharmacological modulation of EGFR might be a useful tool for treating neuroinflammatory diseases characterized by sPLA 2 -IIA accumulation.

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“…HB-EGF, EGF, and EGFR expression increase in the SVZ and the areas surrounding the injury (11,43,258,390,450), and EGF or TGF-␣ infusion can promote axon regeneration (217, 599), while specific forebrain HB-EGF deletion exacerbates brain injury (407). Although EGFR tyrosine kinase inhibitors, such as AG1478 and PD168393, promote neurite growth in in vitro axon growth inhibitory screening, these effects may result from indirect and/or offtarget effects of these inhibitors and are likely not related to EGFR inactivation, since administration of EGFR siRNA could not reproduce this effect (43).…”

Section: Egfr and Cns Injury Recoverymentioning

confidence: 99%

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Chen

Zeng

Forrester

et al. 2016

Physiological Reviews

219

156

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The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.

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Forebrain specific heparin-binding epidermal growth factor-like growth factor knockout mice show exacerbated ischemia and reperfusion injury

Cited by 24 publications

References 44 publications

Role of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Light-Induced Photoreceptor Degeneration in Mouse Retina

Role of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Light-Induced Photoreceptor Degeneration in Mouse Retina

Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

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