Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia.
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), 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-1 α 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.
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. famakinb@ninds.nih.gov.
Bolanle
B
Famakin
Yongshan
Y
Mou
Maria
M
Spatz
Modinat
M
Lawal
John
J
Hallenbeck
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011897:Random Allocation; D015398:Signal Transduction / Q000235:genetics*; D051193:Toll-Like Receptors / Q000502:physiology*
D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors