Toll-like receptor-4 antagonism mediates benefits during neuroinflammation.

Abstract

Neuroinflammation following immune activation in the central nervous system (CNS) leads to neuronal loss in specific areas of the CNS resulting in neurodegenerative disorders. Thus, fine tuning the immune responses within the brain is essential, because most of the brain diseases are associated with chronic inflammation, aberrant microglia activation that follows inappropriate T cell activation and polarization. Brain's immune cells, microglia, are sensitized to extrinsic and intrinsic stimuli mediating neuroinflammation contributing to the removal of pathogen/injurious stimuli and initiate healing process in the CNS. However, dysregulation of the inflammatory response leads to bystander tissue damage. During sterile and infectious acute brain injuries chronic inflammation exacerbates neurodegeneration and contributes to pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, depression, sickness behaviour, diminished cognition and memory. Neuroinflammation in the CNS can be mediated by many of the factors including pattern/danger-associated molecular patterns (PAMPs and DAMPs) are recognised by the various classes of pattern recognition receptors (PRRs). Among the group of PRRs, the toll-like receptor-4 (TLR4) is crucially involved in neuropathology. Microglia are the only cell type in resting CNS that express TLR4 mediating neuronal damage (Lehnardt et al., 2003). Its upregulation is reported in neuronal injuries and neurodegenerative diseases while the deficiency protects against neurodegeneration and shows increased survival of neurons. Mutation in the TLR4 decreases microglial activation and preserves cognitive functions in mouse model of Alzheimer's disease.