A New Role for Downstream Toll-like Receptor Signaling in Mediating Immediate Early Gene Expression during Focal Cerebral Ischemia

Abstract

To better understand the role of downstream Toll-like receptor (TLR) signaling during acute cerebral ischemia, we performed cDNA microarrays, on brain RNA, and cytokine arrays, on serum, from wild type (WT), MyD88 À / À and TRIF-mutant mice, at baseline and following permanent middle cerebral artery occlusion (pMCAO). The acute stress response pathway was among the top pathways identified by Ingenuity Pathway Analysis of microarray data. We used real-time polymerase chain reaction to confirm the expression of four immediate early genes; EGR1, EGR2, ARC, Nurr77, in this pathway, and insulin degrading enzyme (IDE). Compared to WT, baseline immediate early gene expression was increased up to10-fold in MyD88 À / À and TRIF-mutant mice. However, following pMCAO, immediate early gene expression remained unchanged, from this elevated baseline in these mice, but increased up to 12-fold in WT. Furthermore, expression of IDE, which also degrades b-amyloid, decreased significantly only in TRIF-mutant mice. Finally, sE-Selectin, sICAM, sVCAM-1, and MMP-9 levels were significantly decreased only in MyD88 À / À compared with WT mice. We thus report a new role for downstream TLR signaling in immediate early gene expression during acute cerebral ischemia. We also show that the TRIF pathway regulates IDE expression; a major enzyme that clears b-amyloid from the brain.

MiR‐377 Regulates Inflammation and Angiogenesis in Rats After Cerebral Ischemic Injury

“…Moreover, dual‐luciferase reporter assay confirmed that miR‐377 can directly regulate EGR2 expression by binding to its 3′UTR. Previous studies have demonstrated that EGR2 expression increased 10.9‐fold in the rats at 3 h after permanent middle cerebral artery occlusion (pMCAO) [Famakin et al, ]. Our data showed the expression of EGR2 was significantly increased in the MCAO rats and in the OGD‐treated microglia cells.…”

The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia

“…Toll-like receptor 4 (TLR4)-mediated neuroinflammation figures centrally in a growing list of inflammatory and degenerative conditions of the central nervous system (CNS), including traumatic brain injury, ischemic stroke, hemorrhagic stroke, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, and amyotrophic lateral sclerosis [ 1 – 4 ]. These conditions share the common feature that endogenous molecules associated with injury, known as alarmins or danger-associated molecular patterns (DAMPs), converge upon TLR4 and initiate potentially deleterious inflammatory cascades [ 2 , 5 , 6 ].…”

Myeloid differentiation primary response gene (MyD) 88 signalling is not essential for intestinal fibrosis development

“…MyD88-signalling is an inducer of MMP-9 expression 27 , 28 . As MMPs are involved in mucosal fibrosis we determined the expression of tissue remodeling protease MMP-9 and the tissue inhibitor of metalloproteinases TIMP-1 in intestinal transplants by real-time PCR.…”

“…While Mmp9 expression was increased upon development of fibrosis we did observe a significant difference between the grafts from both genotypes. MyD88-signalling is a potent inducer of MMP-9 expression 27 , 28 . Likewise, GFP-Tg grafts transplanted into MyD88 −/− recipients yielded significantly lower expression levels than the MyD88 −/− grafts in GFP-Tg recipients.…”