Mini-Review: Neuroinflammation and Toll-Like Receptors

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The Role of TLRs in Neuroinflammation

The role of TLRs in neuroinflammation

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What is Neuroinflammation?

Is neuroinflammation a cause of or a consequence of neurodegeneration and is it protective or destructive?  Acute neuroinflammation is required for the removal of amyloid beta (Aβ) plaques by microglia. However, on-going neuroinflammation results in glial dysfunction and neuronal compromise. Therefore, the time period and intensity of the inflammatory response is critical with respect to whether the response is protective or destructive.

Injury to the brain leads to the activation of repair pathways such as the recovery of the neuronal network, enhancing plasticity and providing alternative methods of performing tasks affected by the loss of brain tissue. Neuroinflammation is the response by glial cells (e.g. microglia and astrocytes) to infection or injury as part of the innate immune system. Activated glial cells produce pro-inflammatory cytokines, enzymes, and adhesion molecules - a response aided by TLRs.

Ischemic mice negative for tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), show a larger amount of necrotic tissue when their inflammatory response is activated, indicating a protective role of the inflammation mediator products TNFα and IL-6. In addition to that, other cytokines like the IL-1 family play a detrimental role in inflammation; e.g. the deletion of IL-1α and IL-1β in mice reduces ischemic brain damage (Boutin et al. 2001). IL-1 is expressed after injury and in an NF-kB dependent manner. It therefore appears that timing, as well as specific cytokine expression, which is often regulated by TLR signaling, is crucial in determining whether inflammation helps or hinders repair.

Toll Like Receptors and Aging

During aging, secretion of pro-inflammatory cytokines is increased, whereas levels of anti-inflammatory cytokines decrease. Similarly TLR signaling is also altered during aging. This suggests that TLRs and inflammation are important factors in the onset of all kinds of age related diseases. 

What are toll like receptors?

TLRs play a key role in the development and regulation of inflammation, neurodegeneration, and brain trauma. They are crucial components in activating the innate immune response against invading pathogens in addition to playing a key role in neuronal degeneration, neurogenesis, and neurite outgrowth. All these roles taken together suggest an important role in maintaining neuronal plasticity. In total 11 human and 13 mouse TLRs have been identified, all belonging to the pattern recognition receptor (PRR) family, along with other receptors such as CD206, and NALP  (a Nod-like receptor). TLRs are expressed on a large variety of immune-related cells, including microglia, astrocytes, oligodendrocytes, and neurons in the brain. Their expression patterns are dependent on the presence of pathogens, cytokines, and environmental stresses.

TLRs are either expressed on the cell surface (TLR1, 2, 4, 5, and 6) or in endosomal vesicles (TLR3, 7, 8, and 9). Characteristic for all TLRs is a leucine-rich extracellular domain, which is involved in recognizing pathogen associated molecular patterns (PAMPs). Also conserved is a cytoplasmic Toll-IL-1 receptor (TIR) domain, which initiates downstream signaling via mediating interactions between TLRs and TIR-adapter proteins like myeloid differentiation factor 88 (MyD88), TIR-adapter proteins (TIRAP), TIR-domain-containing adapter-inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM). These interactions result in the upregulation and expression of inflammation regulating transcription factors such as NF-kB.

TLR4 is highly conserved from Drosophila melanogaster to humans. The active form of TLR4 is able to activate the NF-kB pathway thereby leading to the expression of NF-kB-dependent inflammatory genes and CD80, which are crucial in a T cell reponse.These are all necessary for the activation of naïve T lymphocytes, key players in an innate immune  response (Medzhitov et al. 1997). Repeated stress exposure upregulates TLR4 expression suggesting a key role of TLR4 in stress-induced NF-κB activation, iNOS and COX-2 upregulation, and cellular oxidative/nitrosative damage responses. TLR4 signaling also affects IL-1β, IL-10, and IL-7 levels.

TLRs form either homo- or heterodimers and are categorized into three main groups (Table 1) according to the specific PAMP motif they recognize. These classes are:

1. TLRs recognizing lipids.
2. TLRs activated by protein ligation.
3. TLRs recognizing bacterial and viral nucleic acids.

Table 1. TLR overview.

The TLR Pathway

After PAMP recognition, TLR signaling is mediated in either a MyD88 dependent or MyD88 independent/Trif dependent manner. MyD88 is an adapter protein that mainly interacts with TIRAP/ MyD88-adapter-like (Mal) and TRAM proteins and plays a crucial role in enabling the recruitment of the IL-1R associated kinases (IRAK ) -1, 2, 3, 4. TIRAP /Mal and TRAM are also required for the activation of TRIF dependent signaling. All TLRs signal via the MyD88-dependent pathway, except for TLR3 which signals exclusively via TRIF.

Key steps in both MyD88 and TRIF mediated TLR signaling have been outlined below using TLR4 as an example. The outcome of both pathways is the activation of IRF3, NF-kB, and AB-1, which regulate the expression of pro-inflammatory cytokines and type 1 IFN. 

MyD88-dependent pathway 

• Boutin, H et al. (2001). Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 21 (15), 5528-5534.
• Medzhitov R et al.(1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397.
• Okun E et al. (2009). Toll-like Receptors in neurodegeneration​. Brain Res Rev 59(2), 278-292.
• Schonberg DL et al. (2007). Oligodendrocyte generation is differentially influenced by toll-like receptor (TLR) 2 and TLR4-mediated intraspinal macrophage activation. J. Neuropathol. Exp. Neurol 66, 1124-1135.
• Setzu A et al. (2006). Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia 54, 297-303.