This post initially appeared on Science Blogs

If you've ever rolled your ankle (as I have many times), you have a visceral knowledge of inflammation. Clinically, inflammation is the redness, swelling, heat and pain that's associated with injury. From an immunologist's perspective, it's the set of molecular events that get the immune system going. All of the clinical systems associated with inflammation are due to increased vascular permeability, which is just a fancy way of saying leaky blood vessels. Actually, "leaky" implies that it's uncontrolled, when in fact there's a very orchestrated set of events that recruit immune cells and other helpful factors to the site of an injury.

I've talked a lot about inflammation in a lot contexts, but generally, I think of it as being triggered by the activation of a pattern recognition receptor (PRR) in response to a potential pathogen. When you get a cut, some bacteria are bound to get into it and set off the alarms - alarms that are triggered by "pathogen associated molecular patterns" (PAMPs). But in reality, there are a lot of things that trigger inflammation in the absence of bugs - the rolled ankle I mentioned above is a perfect example. Since there are no bugs involved, it's called sterile inflammation:

It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns [DAMPs]. The sterile inflammation that ensues either resolves the initial insult or leads to disease.

DAMPs are the sterile equivalent of PAMPs, and it turns out that they activate inflammation in many of the same ways. Inflammation is usually helpful. Most infections are resolved once the neutrophils swarm in and lay down the napalm, and if they're insufficient, the same signals that trigger inflammation also activate the adaptive immune system. But inflammation is also destructive. Many of the strategies for eliminating bugs also cause tissue damage. Usually, a bit of damage is a small price to pay to clear an infection, but if inflammation remains unresolved, it can be a serious issue.

Take for instance, asbestos. Last week, I talked about the inflammasome, which can be triggered in response to membrane damage. When macrophages try to eat the asbestos crystals, they get frustrated and react by spewing out some inflammatory cytokines. Since the asbestos can't actually be eliminated, this process continues, and the lungs become chronically inflamed (how this can lead to cancer is a whole 'nother post). A similar problem may occur in obese individuals (macrophages have trouble mopping up the free fat when adipocytes die) leading to diabetes. Many human diseases are associated with inflammation in the absence of infection. From autoimmunity to sprained ankles, it would be useful to know how the early events in inflammation are triggered. In some cases, known PRR's have been implicated, but by no means proven.

Based on our current understanding, we propose three, not necessarily mutually exclusive, mechanisms by which sterile endogenous stimuli trigger inflammation: activation of PRRs by mechanisms similar to those used by microorganisms and PAMPs; release of intracellular cytokines and chemokines, such as IL-1α, that activate common pathways downstream of PRRs; and direct activation by receptors that are not typically associated with microbial recognition

Of course, the stated goal for understanding these processes is always the potential for therapeutics, and the authors spend a good deal of time discussing possible targets, but I think the underlying questions are interesting as well. Did PRR's evolve to combat microbes, and then get co-opted to deal with sterile injury, or was it the other way around? Or is sterile inflammation and unintended consequence? Those questions are hard to answer though, and I think we're too early in our understanding to make any meaningful stabs. As is becoming my habit, I'll leave you with the authors' concluding remarks:

Much progress has been made in identifying some of the triggers of sterile inflammation. Many questions remain, including the relative importance of the different DAMPs in their biological activity, whether they differentially activate downstream signalling pathways and the molecular basis for their recognition. Whether there are additional unidentified endogenous DAMPs that may be implicated in disease is also unknown. Finally, further studies are needed to understand how the different inflammatory signalling pathways (mediated by TLRs, inflammasomes and IL-1R) interact to mediate the sterile inflammatory response and how they may be modulated for the benefit of the host.

Chen GY, & Nuñez G (2010). Sterile inflammation: sensing and reacting to damage. Nature reviews. Immunology, 10 (12), 826-37 PMID: 21088683

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