TLRs can act alone or heterodimerize to create specific responses to a given stimuli. All TLRs except TLR3 signal through the adaptive protein Myd88, which leads to the induction of NF-κB and the release of cytokines, such as IL-1β, TNF-α, and IL-12. Conversely, TLR3 cannot activate Myd88 but signals through a TRIF-dependent pathway, Ipatasertib manufacturer leading to the induction of IRF3 and the production of other cytokines, such as IFNβ. TLR4 can also signal through TRIF with the help of the adaptor protein TRAM. Both Myd88 and TRIF-dependent signaling pathways can also engage
mitogen-associated protein kinase (MAPK) pathways, including ERK1/2, p38, and JNK, which lead to the stimulation of cell growth and
the induction of inflammatory cytokine production (Brown et al., 2011). For an in-depth review of TLR pathways, the reader can consult Hanke and Kielian (2011) and Rivest (2009). A function for NLRs in neuroinflammation is a rather recent discovery. Mostly known for their functions in the spleen and lymph nodes, there is much still to learn of their roles in the CNS. Among the 21 members of the NLR family, NLRP1-3, NLRP6, NLRP10, NOD1, Bioactive Compound Library and NOD2 show the highest level of expression in the CNS, mostly in microglia but also in astrocytes, oligodendrocytes, neurons, and endothelial cells for some subtypes (Rosenzweig et al., 2011). almost Among these, NLRP3 and NOD2 have been the most studied so far because of their implication in autoinflammatory diseases of the CNS (Deane et al., 2012). NOD2 can respond to muramyl dipeptide (MDP, a PAMP from bacterial cell walls) and viral ssRNA (Ribes et al., 2012). NOD2 activates NF-κB transcription through the adaptor protein RICK, which leads to the production of proinflammatory cytokines in response to MDP (Ribes et al., 2012). In response to viral ssRNA, NOD2 activates the IRF3 transcription factor with the MAVS
adaptor protein, leading to the release of type 1 interferons (Strober and Watanabe, 2011). NLRP3 is normally in a repressed state, bound to specific chaperone proteins. The presence of an array of different signals can liberate and therefore activate NLRP3. Such signals include PAMPs, DAMPs, and intact pathogens (Zambetti et al., 2012). Upon its release, NLRP3 activates the inflammasome, a complex of proteins that includes caspase-1, leading to the release of active IL-1β from a precursor (Zambetti et al., 2012). The final type of pattern recognition receptors, RIG-1-like receptors, is geared toward the recognition of viral nucleic acids in the cytoplasm (Creagh and O’Neill, 2006). Three members of this family have been described so far: retinoic acid-induced gene 1 (RIG-1), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2).