Every few months, it comes my time to give a literature review during our lab meetings. As this past Monday was my turn again, I’ve decided to take the opportunity to share what I learned on a particular topic in the blogosphere as well. I realize these posts will not get as many comments since not everyone is as into bacteria/cell death/kickass proteins as I am, but it feels good to blog about the research others are doing and not just about my cares and woes all the time! So here comes the serious science post:
Pyroptosis could be called the hottest thing in cell death. Two recent reviews in Nature Immunology1 and Nature Reviews Microbiology2 (of which it made the cover, see below) covered this caspase-1-depedent cell death pathway.
Not familiar with caspases? These proteins are most well-known for their role in apoptosis or programmed cell death, which is vital for embryonic development and the removal of damaged cells. Caspases are cytseine proteases and are self-activating, i.e they are able to cleave themselves to their active form. Pyroptosis, like apoptosis, is also a form of programmed cell death, but the end result of that death is very different. Pyroptosis is crucial to eliciting inflammation when cells are faced with a microbial infection (including such nastys as Salmonella, Legionella, and Francisella) to mount the reponse necessary to clear the invader as quickly as possible. Think fever, cytokine and chemokine expresion, immune cell activation, etc.
Caspase-1 is required for pyroptosis, as it is responsible for the activation and secretion of the inflammatory cytokines IL-1beta and IL-18. Cell death occurs upon caspase-1 activation because during pyroptosis an unidentified caspase-1 dependent nuclease cleaves the DNA into diffuse fragments and caspase-1 dependent pores form in the cell wall, causing swelling and eventual lysis. This is all crucial to alerting the immune system that there’s an intruder and he needs to be captured and burned at the stake. If all goes well, the infection is resolved, memory T cells are made and the inflammation response is “put out” before it gets out of hand…
In the case of excessive or aberrant inflammation, the consequences can be extremely damaging to host tissues and organs. Such unwanted inflammation may manifest as a host of autoinflammotry and autoimmune conditions and has been implicated in myocardial infarction and inflammatory bowel disease. Inappropriate inflammation can be due to mutations in the proteins responsible for associating with caspase-1 and allowing its activation, the Nod-like receptors (NLRs), or the persistence of a sterile inflammatory signal. So it will come as no surprise that those in the applied sciences have an interest in understanding the body’s mechanisms for controlling inflammation.
Vertex pharmceuticals (San Francisco), has completed phase II clinical trials with a compounds called VX-765, which appears to inhibit active caspase-1, dampening the inflammatory response. Also, a recent letter in Nature shed further light on how the body controls inflammation through T cells. Guarda and coworkers3 found that CD4+ memory T cells have the ability to inhibit caspase-1 activation and the release of caspase-1 dependent inflammatory cytokines under certain stimuli such as B. anthracis lethal toxin, LPS and ATP. This was a surprise as it had been expected that CD4+ regulatory
T cells (Tregs) would be responisble for this inhibition. Additionally, several tumor necrosis factor (TNF) proteins, such as CD40L, RANKL, and LIGHT, exhibited the same inhibitory ability alone as the CD4 memory T cells.
As our understanding of the inflammatory response and underlying mechanisms that regulate it improve, new opportunities for anti-inflammatory targets and treatments may emerge. The challenge will be to control unwanted inflammation while leaving the patient’s capacity for appropriate inflammation and immune cell activation in the face of infection undiminished.
References
1. Franchi, L. Nat Immunol. 2009
2. Bergsbaken, T. Nat Rev Microbiol. 2009
3. Guarda, G. Nature. 2009
Interesting post- is anything known about what exactly about infection triggers the pyroptosis pathway? Will take a look at those refs, thanks!
The Nod-like receptors (NLRs) mediate recognition of signals in the cytosol of the cell (while toll-like receptors recognize signals from the cell surface). These signals can include the presence of intracellular bacteria (such as salmonella typhimurium) and the proteins injected into the cell by Type III secretion systems. There are many different signals that can be recognized by different NLR proteins, and I believe the identification of these interactions is still on-going.