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(Circulation. 2007;115:1599-1608.)
© 2007 American Heart Association, Inc.

Stroke

Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke

Javier R. Caso, BSc^*; Jesús M. Pradillo, BSc^*; Olivia Hurtado, PhD; Pedro Lorenzo, MD, PhD; María A. Moro, PhD; Ignacio Lizasoain, MD, PhD

From the Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.

Correspondence to Dr Ignacio Lizasoain, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense Madrid, 28040 Madrid, Spain. E-mail ignacio.lizasoain{at}med.ucm.es

Received November 22, 2005; accepted January 5, 2007.

Background— Stroke is the second to third leading cause of death. Toll-like receptor 4 (TLR4) is a signaling receptor in innate immunity that is a specific immunologic response to systemic bacterial infection and cerebral injury. The role of TLR4 in brain ischemia has not been examined yet. We have therefore investigated whether cerebral ischemia and inflammation produced by permanent occlusion of the middle cerebral artery differ in mice that lack a functional TLR4 signaling pathway.

Methods and Results— Permanent occlusion of the middle cerebral artery was performed on 2 strains of TLR4-deficient mice (C3H/HeJ and C57BL/10ScNJ) and respective controls (C3H/HeN and C57BL/10ScSn). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected 24 hours and 7 days after stroke. When compared with control mice, TLR4-deficient mice had lower infarct volumes and better outcomes in neurological and behavioral tests. Mice that lacked TLR4 had minor expression of stroke-induced interferon regulatory factor-1, inducible nitric oxide synthase, and cyclooxygenase-2, mediators implicated in brain damage. The levels of interferon-ß and of the lipid peroxidation marker malondialdehyde were also lower in brains from TLR4-deficient mice than in those from control mice. In addition, the expression of matrix metalloproteinase-9, which is induced and mediates brain damage, was also reduced in TLR4-deficient mice after experimental stroke.

Conclusions— TLR4-deficient mice have minor infarctions and less inflammatory response after an ischemic insult. These data demonstrate that TLR4 signaling and innate immunity are involved in brain damage and in inflammation triggered by ischemic injury.

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