Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage

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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. Methods 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. Results 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. Conclusions 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.

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Published 01 January 2012
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Linet al.Journal of Neuroinflammation2012,9:46 http://www.jneuroinflammation.com/content/9/1/46
JOURNAL OF NEUROINFLAMMATION
R E S E A R C HOpen Access Heme activates TLR4mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage 1,421 11 4*1 3 Sen Lin, Qing Yin, Qi Zhong , FengLin Lv , Yu Zhou , JingQi Li , JingZhou Wang , Bingyin Suand 1* QingWu Yang
Abstract Background: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. Methods: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B were measured by Western blot and EMSA, animal behavior was evaluated by animal behavioristics. /Results:mice had restrained ICHinduced brain damage showing in reducedCompared to WT mice, TLR4 cerebral edema and lower neurological deficit scores. Quantification of cytokines including IL6, TNFaand IL1b /− −/− −/and assessment of macrophage infiltration in perihematoma tissues from TLR4, MyD88and TRIFmice /showed attenuated inflammatory damage after ICH. TLR4mice also exhibited reduced MyD88 and TRIF expression which was accompanied by decreased NFB activity. This suggests that after ICH both MyD88 and TRIF pathways might be involved in TLR4mediated inflammatory injury possibly via NFB activation. Exogenous hemin administration significantly increased TLR4 expression and microglial activation in cultures and also exacerbated /brain injury in WT mice but not in TLR4mice. AntiTLR4 antibody administration suppressed hemininduced microglial activation in cultures and in the mice model of ICH. Conclusions:Our findings suggest that heme potentiates microglial activationviaTLR4, in turn inducing NFB activationviathe 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. Keywords:Tolllike receptor 4, MyD88, TRIF, Inflammation, Intracerebral hemorrhage, Heme
* Correspondence: subingyin@yahoo.com.cn; yangqwmlys@hotmail.com Contributed equally 1 Department of Neurology, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China 4 Department of Development and Regeneration Key Laboratory of Sichuan Province, Department of Histoembryology and Neurobiology, Chengdu Medical College, Chengdu 610083, PR China Full list of author information is available at the end of the article
© 2012 Lin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.