Journal of neuroinflammation, 2012-03, Vol.9 (1), p.46-46, Article 548
2012
Details
- Autor(en) / Beteiligte
- Titel
- Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage
- Ist Teil von
- Journal of neuroinflammation, 2012-03, Vol.9 (1), p.46-46, Article 548
- Ort / Verlag
- England: BioMed Central Ltd
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- SpringerLink (Online service)
- Beschreibungen/Notizen
- Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced neurological deficits; however, the signaling pathways are not apparent by which the upstream cellular events trigger innate immune and inflammatory responses that contribute to neurological impairments. Toll-like receptor 4 (TLR4) plays a role in inflammatory damage caused by brain disorders. In this study, we investigate the role of TLR4 signaling in ICH-induced inflammation. In the ICH model, a significant upregulation of TLR4 expression in reactive microglia has been demonstrated using real-time RT-PCR. Activation of microglia was detected by immunohistochemistry, cytokines were measured by ELISA, MyD88, TRIF and NF-κB were measured by Western blot and EMSA, animal behavior was evaluated by animal behavioristics. Compared to WT mice, TLR4(-/-) mice had restrained ICH-induced brain damage showing in reduced cerebral edema and lower neurological deficit scores. Quantification of cytokines including IL-6, TNF-α and IL-1β and assessment of macrophage infiltration in perihematoma tissues from TLR4(-/-), MyD88(-/-) and TRIF(-/-) mice showed attenuated inflammatory damage after ICH. TLR4(-/-) mice also exhibited reduced MyD88 and TRIF expression which was accompanied by decreased NF-κB activity. This suggests that after ICH both MyD88 and TRIF pathways might be involved in TLR4-mediated inflammatory injury possibly via NF-κB activation. Exogenous hemin administration significantly increased TLR4 expression and microglial activation in cultures and also exacerbated brain injury in WT mice but not in TLR4(-/-) mice. Anti-TLR4 antibody administration suppressed hemin-induced microglial activation in cultures and in the mice model of ICH. Our findings suggest that heme potentiates microglial activation via TLR4, in turn inducing NF-κB activation via the MyD88/TRIF signaling pathway, and ultimately increasing cytokine expression and inflammatory injury in ICH. Targeting TLR4 signaling may be a promising therapeutic strategy for ICH.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1742-2094eISSN: 1742-2094DOI: 10.1186/1742-2094-9-46Titel-ID: cdi_doaj_primary_oai_doaj_org_article_27431b95ecf34278afc5dde16c40c2ef
- Format
- –
- Schlagworte
- Adapter proteins, Adaptor Proteins, Vesicular Transport - deficiency, Adaptor Proteins, Vesicular Transport - metabolism, Analysis, Animal behavior, Animals, Animals, Newborn, Antibodies, Monoclonal - therapeutic use, Blood-brain barrier, Brain damage, Brain injuries, Cells, Cultured, Cerebral Cortex - cytology, Cerebral Hemorrhage - complications, Cerebral Hemorrhage - drug therapy, Cytokines, Cytokines - metabolism, Electrophoretic Mobility Shift Assay, Enzyme-Linked Immunosorbent Assay, Enzymes, Experiments, Heme, Heme - pharmacology, Inflammation, Inflammation - etiology, Intracerebral hemorrhage, Lipopolysaccharides - pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia - drug effects, MyD88, Myeloid Differentiation Factor 88 - deficiency, Myeloid Differentiation Factor 88 - metabolism, Neurologic Examination, Neurosciences, NF-kappa B - metabolism, Physiological aspects, RNA, Messenger - metabolism, Rodents, Signal Transduction - physiology, Statistics, Nonparametric, Studies, Time Factors, Toll-like receptor 4, Toll-Like Receptor 4 - deficiency, Toll-Like Receptor 4 - genetics, Toll-Like Receptor 4 - immunology, Toll-Like Receptor 4 - metabolism, Toll-like receptors, TRIF, Up-Regulation - drug effects, Up-Regulation - genetics, Up-Regulation - physiology