Toll‑Like Receptors
Toll-like receptors are pathogen-detection and clearance receptors.
Toll-like receptors (TLRs) are essential regulators of innate immunity
and are involved in the initiation of the inflammatory response in the
event of infection. TLRs initiate a series of signaling cascades in
leukocytes in response to DAMPs or pathogen-associated molecular
patterns (PAMPs), resulting in enhanced cytokine production and
activation (Okada & Suzuki, 2017; Tang, Kang, Coyne, Zeh & Lotze,
2012). TLR4 activation by DAMPs such as OxyHb metabolites and
fibrinogen, which are produced during aneurysm rupture, has been linked
to the pro-inflammatory state that follows SAH (Khey, Huard & Mahmoud,
2020). TLR4 or its related pathways were inhibited with a variety of
medicines in experimental SAH, which reduced vasospasm, provided
neuroprotection, and offered anti-inflammatory effects (Chang, Wu &
Kwan, 2014; Liu, Yang, Pan, Liu & Ma, 2016). Fluoxetine was discovered
to reduce neuroinflammation and improve neurological function in SAH
rats. TLR4/MyD88/NF-κB signaling pathway is one of the probable pathways
involved (Liu et al., 2018). TLR4-deficient mice had reduced infarct
volumes and improved neurological and behavioral outcomes, according to
a research (Caso, Pradillo, Hurtado, Lorenzo, Moro & Lizasoain, 2007).
TLR4 knockout mice had lower levels of mediators linked to brain injury,
including stroke-induced IRF-1, iNOS, and cyclooxygenase 2. In the
brains of TLR4-deficient rats, IFN- and the lipid peroxidation marker
malondialdehyde were found to be lower. After an artificial stroke, the
researchers found that in TLR4-deficient rats, the matrix
metalloproteinase 9 expression which helps to cause brain injury was
attenuated (Caso, Pradillo, Hurtado, Lorenzo, Moro & Lizasoain, 2007).
TLR4 signaling appears to control the severity of ischemia-induced
neuronal damage, suggesting that TLR4 could be a target for SAH
prevention and treatment (Caso, Pradillo, Hurtado, Lorenzo, Moro &
Lizasoain, 2007). TREM-1 was found to be dynamically raised in the brain
after eSAH, especially in microglia and vascular endothelial cells,
implying that it may improve EBI through interacting with the TLR4
pathway (Sun et al., 2021).