This post initially appeared on Science Blogs

Normally, I would feel woefully unqualified to analyze a Nature Neuroscience paper, but I'm going to do it anyway. How could I pass it up? It features a Toll-like receptor!

Toll-like receptors are typically expressed in immune cells to regulate innate immunity. We found that functional Toll-like receptor 7 (TLR7) was expressed in C-fiber primary sensory neurons and was important for inducing itch (pruritus), but was not necessary for eliciting mechanical, thermal, inflammatory and neuropathic pain in mice.

TLR's are on the front lines of immune defense. They are present on many cells types, especially immune cells, and alert the cell that something foreign is in the area. Evolution has selected them to recognize things that are found on bacteria, viruses and fungi, but not on our own cells. If a cell expresses a TLR, and that TLR binds to its ligand, that usually tells the cell that something is wrong, and an immune response should be triggered.

But a TLR is just a receptor, and there's no reason, in principal, that it couldn't be co-opted for other uses. And that seems to be what these authors found

For a long time, TLR7 has kinda been the unwanted stepchild of the innate immunity field. Some folks had discovered a couple of ligands that induced anti-viral immunity in immune cells, but those ligands don't follow the typical mold of being associated with pathogens. Mice that lack TLR7 don't have a profound defect in combating viruses, and most people tend to ignore TLR7 entirely.

It made sense to look for immune functions, since other members of that receptor family have immune functions, but there's no reason why TLR7 must be an immune receptor, and these authors found something altogether different. When imiquimod - one of the ligands originally described for TLR7 - is injected into mice, the mice get itchy. Mice that don't have TLR7 don't get as itchy.

Based only on what I've told you, this might not seem that surprising, but this is a completely novel role for a TLR. If you inject the ligands for other TLRs (like lipopolysaccharide for TLR4), you get massive inflammation, not itching. Further, they showed that TLR7 was required for several other (though not all) "pruritic" (itch-inducing) agents.

The thing that I found most surprising is that TLR7 is actually expressed on the sensory neurons of mice, and that the TLR7 seems to be necessary to generate an action potential in response to imiquimod. There's a lot to follow up on here, but these guys are neuroscientists, and so the things I'd love to see as an immunologist are not necessarily on their list of priorities. Still - I've always been fascinated by neuroscience - maybe now I'll have an excuse to move in that direction as a post-doc.

Liu T, Xu ZZ, Park CK, Berta T, & Ji RR (2010). Toll-like receptor 7 mediates pruritus. Nature neuroscience PMID: 21037581

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