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
- Log in to post comments
As someone who studies TLRs in innate immunity, I gotta say you reveal your bias. Toll is, after all, critical for development of drosophila. So there'd be no reason to expect that all TLRs will function only in immunity; even if 'itch' sensation isn't exactly something I would have guessed a priori.
This is kind of an awesome paper, I'm glad you brought it to my attention.
What is weird to me is that TLR7 is an endosomal TLR, yet it is participating in this. Although, from the in situ in the paper, it looks more like cell surface. How reliable are TLR7 antibodies? I know there's a decent amount of controversy when it comes to some TLR antibodies and in situ results.
Where does MrgprA3 localize?
On the other hand, if it *is* on the cell surface, how is it responding to the lysomotrophic chloroquine? Or could Cq go into the cell, meet TLR7, and cause it to be trafficked to the cell surface to interact with MrgprA3 et al?
I'm dumb about neuroscience. Does achieving inward currents involve endosomes somehow?
This is all itching my brain with the weirdness.
P.S. I feel bad for the hapless grad student/postdoc/whoever had to count scratches for 30min.
Becca - you make many good points. Clearly, I have an immunological bias, but I wanted to highlight this paper specifically because it shows that we can often paint ourselves into a corner when we stick to accepted dogma.
TLR antibodies are generally terrible - the structure is comprised of lots of leucine-rich repeats, and they are fairly conserved, so there are a lot of issues with specificity. I don't know what antibody they used for the microscopy, but the figure where they show "co-localization" is by single-cell PCR - meaning that TLR7 and MrgprA3 is expressed in the same cell, but says nothing about where in the cell it's located (not the definition of "co-localization" I would use - maybe that's how it's used in neuroscience?).
As for where it is, I think this is the first paper to look at neurons in this context. Most of the cell biology of TLR's has been worked out in macrophages and DCs, but there's some evidence that endosomal TLR's like TLR9 are expressed on the cell surface on other cell types like epithelial cells. There's no reason the same couldn't be true for TLR7.
[richarddawkins.net link deleted - KB]
atheists, we're gonna cut off your heads...
THE HIGH PRICE OF REVOLUTION
[Youtube link deleted - KB]
Can you get AIDS/HIV if you have Lupus or another auto-immune disorder? BTW I am not a Doctor.... Just a Artist. ":P
@ christopher: As far as I know, yes. Though I imagine that if HIV were left untreated, the symptoms of autoimmunity would start to diminish as your immune system shut down.
TLR antibodies are generally terrible - the structure is comprised of lots of leucine-rich repeats, and they are fairly conserved, so there are a lot of issues with specificity. I don't know what antibody they used for the microscopy, but the figure where they show "co-localization" is by single-cell PCR - meaning that TLR7 and MrgprA3 is expressed in the same cell, but says nothing about where in the cell it's located (not the definition of "co-localization" I would use - maybe that's how it's used in neuroscience?).
Well, now I'm glad my boss decided that he didn't want to follow up on the TLR7 thing. His plan was to have me shave the mice and rub them with imiquimod (or gardiquimod) cream, which I would have to get from the University pharmacy, where it's used as a topical treatment for herpes.
So not only would it have been a mortifying and weird experiment, but the poor mice would have been all itchy.
Oh goodie, Mabus dropped by.
Yeah - who exactly is he?
I wonder whether MrgprA3 and other itch receptors are even expressed in TLR7 -/- mice. It may be that TLR7 is involved in development or positioning of the itch receptor-expressing DRG neurons, or that it regulates the transcriptional profile of these neurons. I'm not saying it's not an itch receptor itself, but a lot of experiments need to be done before a direct link can be made.
Another issue to address is whether at least part of its effect on itch sensation relies on other cells, like skin cells near itch communicating neurons. For all we know it mediates an immune response or causes other cells to secrete substances that are detected by DRG neurons. Also, you have the issue of its possible expression downstream of the DRG neurons, perhaps in dorsal horn neurons or somewhere else in the spinal cord.
Excellent information in this the author cited numerous examples where DFO scientists had warned the Minister that ground fish stocks were in a dangerous decline, and these findings were either ignored or suppressed as high quotas continued to be allocated.
Thanks....