Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

Bolanle Famakin, Yongshan Mou, Maria Spatz, Modinat Lawal, Hallenbeck, Hallenbeck John

Description

Deletion of some Toll-like receptors (TLRs) affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT), MyD88 −/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO). Methods Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve) and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results IL-6, keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (G-CSF) and IL-10 were significantly decreased in MyD88 −/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88 −/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88 −/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88 −/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

Sujets

• Myd88
• TRIF
• Cytokine
• Receptor
• Neutrophil granulocyte
• White blood cell

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 11
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Famakinet al. Journal of Neuroinflammation2012,9:174 http://www.jneuroinflammation.com/content/9/1/174

JOURNAL OF NEUROINFLAMMATION

R E S E A R C HOpen Access Downstream Tolllike receptor signaling mediates adaptorspecific cytokine expression following focal cerebral ischemia * Bolanle Famakin , YongshanMou, Maria Spatz, Modinat Lawal and John Hallenbeck

Abstract Background:Deletion of some Tolllike receptors (TLRs) affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined −/− cytokine/chemokine expression and inflammatory infiltrates in wildtype (WT), MyD88and TRIFmutant mice following permanent middle cerebral artery occlusion (pMCAO). Methods:Cytokine/chemokine expression was measured with a 25plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve) and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results:IL6, keratinocyte chemoattractant (KC), granulocyte colonystimulating factor (GCSF) and IL10 were −/− significantly decreased in MyD88mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and GCSF corresponded with a trend toward fewer neutrophils in the brains −/− of MyD88mice. IP10 was significantly decreased when either pathway was disrupted. MIP1αwas significantly −/− decreased in TRIFmutant mice, consistent with TRIFdependent production. Finally, MyD88 mice showed elevations of a number of Th2 cytokines, such as IL13, at baseline, which became significantly decreased following pMCAO. Conclusions:Both MyD88 and TRIF mediate pathwayspecific cytokine production following focal cerebral −/− ischemia. Our results also suggest a compensatory Th2type skew at baseline in MyD88mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. Finally, the MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia. Keywords:MyD88, TRIF, Focal ischemia, MCAO, Cytokines, TLR signaling, Tolllike, Receptor, Neutrophils, Leukocytes

Background Stroke remains a leading cause of death and disability in many parts of the world, including the United States, and approved therapies are currently limited. At the cel lular level, a number of mechanisms, including inflam mation, play a key role in the pathogenesis of a host of neurological diseases and acute cerebral ischemia. Therefore, a potential approach to therapy includes

* Correspondence: [e-mail] Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 5B06, MSC 1401, Bethesda, MD 208921401, USA

attenuating the inflammatory damage that results from cerebral ischemia. In this regard, it is important to study and understand key signal transduction elements in pathways such as the Tolllike receptor (TLR) signaling pathway that lead to activation of major transcriptional mediators of inflammation (,i.e. NFκB and activator protein 1) [1]. The TLR signaling pathway is evolutionarily conserved across several species and was initially identified as im portant in the immune response to infection. Subse quently, the TLR signaling pathway has been shown to play a pivotal role in the inflammatory response follow ing ischemiareperfusion in several organ systems [2,3].

© 2012 Famakin 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.