Abstract
Intracerebral hemorrhage (ICH) is a common type of fatal stroke, accounting for about 15% to 20% of all strokes. Hemorrhagic strokes are associated with high mortality and morbidity, and increasing evidence shows that innate immune responses and inflammatory injury play a critical role in ICH-induced neurological deficits. However, the signaling pathways involved in ICH-induced inflammatory responses remain elusive. Toll-like receptor 4 (TLR4) belongs to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory responses. In this review, we summarize recent findings concerning the involvement of TLR4 signaling in ICH-induced inflammation and brain injury. We discuss the key mechanisms associated with TLR4 signaling in ICH and explore the potential for therapeutic intervention by targeting TLR4 signaling.
Highlights
Intracerebral hemorrhage (ICH) is the least treatable type of stroke and has devastating consequences [1]
Increasing evidence has shown that Toll-like receptor 4 (TLR4) signaling plays important roles in ICH-induced inflammatory brain injury by stimulating activation of microglial cells, infiltration of leukocytes, and production of cytokines and chemokines [28,31]
The TLR4 signaling pathway involved in ICHinduced inflammatory injury includes ligands, TLR4 itself, and its downstream pathways, including adaptor proteins (MyD88 and TIR domain-containing adaptorinducing interferon (TRIF)) and transcription factors, such as nuclear factorκB (NF-κB) [28]
Summary
Intracerebral hemorrhage (ICH) is the least treatable type of stroke and has devastating consequences [1]. Our recent in vivo study shows that activation of TLR4 by heme causes ICH-induced inflammatory injury via the MyD88/TRIF signaling pathway and that effective blockade of TLR4 by its antibody suppresses ICH-induced inflammation [28]. Sansing et al [31] reported increased gene expression of CD36, CSF2 and CX3CL1 in TLR4-knockout mice compared to WT mice Taken together, these studies demonstrate that TLR4 activation is involved in ICH-induced neurological deficits and contributes to the detrimental inflammatory response. Hemin-induced expression of proinflammatory cytokines TNF-α, IL-1β and IL-6 is completely blocked in TLR4-knockout mice [28] These data demonstrate that TLR4 signaling mediates heme-induced inflammatory injury, possibly by activating microglial cells and subsequently releasing proinflammatory cytokines. PPARγ is known to inhibit DNA binding of NF-κB [34,55], which controls expression of proinflammatory cytokines and enzymes, suggesting that the anti-inflammatory effect of PPARγ probably results from inhibition of NF-κB [37,117]
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