Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway

Abstract

Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration. Systemic infection is associated with sustained worsening in many diseases of the CNS, yet the molecular and cellular relationship between infection outside the CNS and potential neuronal loss within the CNS is elusive. Activation of microglia, bone marrow-derived macrophage-like cells that function as the resident immune defense system of the brain (1), is a characteristic feature of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, AIDS dementia complex, and amyotrophic lateral sclerosis as well as ischemia and posttraumatic brain injury (2-4). Neurotoxicity induced by ␤-amyloid or HIV proteins in mixed CNS cultures depends on the presence and activation of microglia (5, 6). Liberatore et al. (7) demonstrated in vivo that microglial inducible nitric oxide synthase plays a crucial role in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.The evolutionarily ancient innate immune system provides the first line of host defense against a large variety of pathogens and also controls many aspects of the adaptive immune response (8). Cells of the innate immune system recognize invariant molecular structures of pathogens termed pathogen-associated molecular patterns through a series of genetically conserved and stable cell-surface receptors related to the Drosophila gene toll that thus are referred to as Toll-like receptors (TLRs) (9).TLR4 functions as the signal-transducing receptor for the endotoxin lipopolysaccharide (LPS) (10), which is a major component of the outer membrane of Gram-negative bacteria. LPS binds to the serum protein LPS-binding protein and the soluble or glycosylphosphatidylinositol-anchored CD14. This complex in turn binds to TLR4 (11) and initiates an intracellular signaling pathway that regulates gene expression through derepression of the transcriptional a...

Microglial Activation in Stroke: Therapeutic Targets

“…Microglia are activated following stimulation of TLR4, which in turn leads to the upregulation of several proinflammatory genes. Work in neonatal mice suggests that TLR4 is necessary for microglial activation following hypoxia/ ischemia, 14 and several groups that have shown that TLR4-deficient mice have better neurological outcomes following experimental stroke. 78 -81 How TLRs are activated in stroke is not precisely known, but endogenous ligands include hyaluronic acid, fibronectin, heat shock proteins (HSP), and heparin sulfate.…”

“…It is important, however, to place this approach in context. Although there is now strong evidence that the inflammatory response can exacerbate ischemic injury, [13][14][15][16][17][18] there is also evidence that some aspects of the inflammatory response are important for tissue repair. These aspects include phagocytosis of cell debris, remodeling of the extracellular matrix, and the release of cytokines and trophic factors.…”

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

“…It is well described that TLR4 is involved in neurodegeneration 12, 14. It was also found that TLR4‐dependent microglial activation mediates spinal cord ischemia–reperfusion injury 11.…”

“…TLR3 also causes downregulation of TLR4 17. TLR4 has been shown to trigger neuronal degeneration and to be involved in several kinds of neurological disorders 12, 14, 15. TLR3 activation with the synthetic RNA analogue poly(I:C) and simultaneous TLR4 downregulation have been described as protective against ischemia– reperfusion injury of the spinal cord 11…”

“…Toll‐like receptor (TLR) 4–dependent microglial activation has been identified in this setting to mediate spinal cord ischemia–reperfusion injury 11. Microglia are spinal resident macrophages and the main cell type in the resting central nervous system that expresses TLR3 and TLR4 12, 13. TLR4 activation has even been shown to trigger neurodegeneration and is thought to be involved in the pathogenesis of several kinds of neurological disorders such as Alzheimer's disease 14.…”