Foley JF. Focus Issue: Inflammatory mechanisms. Science Signaling, 3 March 2015. 8(366):eg2. doi: 10.1126/scisignal.aaa959
This issue of the Science spin-off called Science Signaling is organized around inflammatory pathways, rather than around specific diseases, but these are the same pathways that underlie autoimmune diseases. The research articles in this collection identify pro- and anti-inflammatory mechanisms that may prove promising as targets for new therapies.
Every year, knowledge of the pathways becomes more detailed (and sometimes
overwhelming). This overview identifies some important developmentsScience over the last two or three years.
• Toll-like receptors (TLRs): These are transmembrane pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs), such as the bacterial producs lipopolysaccharide (LPS) and flagellin, and damage-associated molecular patterns (DAMPs) such as histone proteins that are released from damaged or dead cells.
LPS binds to TLR4, stimulating two signaling pathways:
1. The TLR4-MyD88 pathway activates NF-ÎºB, which expresses proinflammatory factors like tumor necrosis factor (TNF), interleukin-6 (IL-6), and IL-1Î².
2. The TLR4-TRIF pathway, in contrast, activates the anti-viral type I interferons (IFNs).
Research reported here shows that the response of the TLR4 receptor depends not on the particular ligand, but on the concentration and timing of the ligand. Other research discovered redundant pathways for identifying RNA viruses.
Excessive production of TNF in response to LPS leads to sepsis. Another TLR receptor blocks the inflammation in a feedback loop, suggesting an anti-inflammatory therapy.
In inflammatory bowel disease, TNF suppresses the synthesis of glucocorticoids. TNF inhibitors restored glucocorticoid synthesis in mice.
• The receptor tyrosine kinaseMer: This enzyme inhibits immune responses to pathogens, and stimulation of Mer and its pathway can reduce inflammation in mice.
• IL-17: Produced by T helper 17 (TH17) cells, IL-17 causes NF-ÎºB inflammatory damage in autoimmune diseases such as rheumatoid arthritis (RA). The deubiquinase A20 inhibits NF-ÎºB activation.
IL-17 receptor (IL-17R) stimulates the production of A20. Mutations in A20 are associated with susceptibility to RA.