Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage
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JOURNAL OF NEUROINFLAMMATION
RESEARCH
Open Access
Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage Sen Lin1,4†, Qing Yin2†, Qi Zhong1, Feng-Lin Lv3, Yu Zhou1, Jing-Qi Li1, Jing-Zhou Wang1, Bing-yin Su4* and Qing-Wu Yang1*
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 realtime 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: 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-a and IL-1b 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-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 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-B 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. Keywords: Toll-like receptor 4, MyD88, TRIF, Inflammation, Intracerebral hemorrhage, Heme
* Correspondence: [email protected]; [email protected] † 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 Co
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