Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury

Abstract

Recent data have implicated inflammation of the cerebrospinal fluid spaces after subarachnoid, intraventricular, and intracerebral hemorrhage to be a critical driver of multiple secondary brain injuries such as hydrocephalus, cerebral edema, and vasospasm. While TLR4-dependent reparative inflammation is an important protective response that can eliminate physical irritants and damaged cells, sustained or inappropriately triggered inflammation can initiate or propagate disease.Areas covered: We review recent advances in our understanding of how TLR4, including its upstream damage-associated molecular patterns and its downstream MyD88-dependent and independent signaling pathways, contributes to hemorrhage-induced inflammation in numerous brain diseases. We discuss prospects for the pharmacotherapeutic targeting of TLR4 in these disorders, including the use of repurposed FDA-approved agents.Expert opinion: TLR4 inhibitors with good blood-brain-barrier (BBB) penetration could be useful adjuncts in post-hemorrhagic hydrocephalus and multiple other diseases associated with brain hemorrhage and inflammation.

Keywords: CSF hypersecretion; Intracerebral hemorrhage; choroid plexus epithelium; intraventricular hemorrhage; neuroinflammation; subarachnoid hemorrhage; toll-like receptor 4.

Figure 1.

Following intracranial hemorrhage, damage-associated molecular patterns (DAMPs), mediated by cluster of differentiation 14 (CD-14) and myeloid differentiation factor 2 (MD-2), bind to TLR4 on the surface of microglia and, in cases of intraventricular hemorrhage (IVH), the choroid plexus epithelium. This stimulation causes TLR4 dimerization with either another TLR4 or TLR2 receptor. This TLR4-complex then binds to the toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) via a TIR-TIR domain interaction. MyD88 interacts with the TIR domains of TIRAP and TLR4, which then binds to and activates IL-1 receptor-associated kinase-4 (IRAK4) and TNF receptor-associated factor 6 (TRAF6). TRAF6 associates with transforming factor-β-activated kinase 1 (TAK1), leading to the activation of IκB kinase (IKK) and subsequent translocation of NF-κB into the nucleus, resulting in the increased production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. These cytokines propagate the inflammatory signal, furthering inflammatory-mediated secondary injury via the recruitment and activation of neutrophils, monocytes, and additional microglia. In IVH, this TLR4-mediated release of proinflammatory cytokines leads to the phosphorylation of Ste20-type stress kinase (SPAK), which subsequently binds and phosphorylates the Na+/K+/2Cl- ion co-transporter (NKCC1) on the choroid plexus. This hyperactivation of NKCC1 leads to CSF hypersecretion and post-hemorrhagic hydrocephalus. Some naturally occurring and synthetic small molecules, antibodies, and antibiotics have demonstrated the potential to target different steps of this cascade and attenuate TLR4-mediated inflammatory signaling in both in vivo and in vitro models.