Crystal clefts, confocal microscopy, and atherosclerosis

June 1, 2010 § Leave a comment

Tim Mitchison comments that this article is one of the most interesting studies he’s seen recently (Duewell et al. (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.  Nature 464 1357-1361).  We’ve known for a long time, of course, that a high level of “bad” cholesterol is a risk factor for atherosclerosis; and atherosclerotic lesions in the walls of arteries typically contain cholesterol crystals.  But the connection between these two observations hasn’t been clear: crystals have been thought to arise only late in disease, after some mysterious other event has started off the development of the plaque.  Part of the problem has been that the solvents used in standard histology dissolve the cholesterol, so identifying crystals has been mostly a matter of spotting the holes where the crystals used to be, rather beautifully called “crystal clefts”.

Duewell et al. used fluorescence confocal microscopy and laser reflection to look a lot more closely at the developing plaques.  They identified tiny cholesterol crystals appearing very early, within 2 weeks after Apo-E-deficient mice were started on a cholesterol-rich diet.  As the crystals appear, so do macrophages, and the macrophages show signs of activating the NLRP3 inflammasome.

What is the NLRP3 inflammasome?  NLRP stands for nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor, a family of nuclear receptors that are part of the innate immune response.  The innate arm of the immune response recognizes patterns that are typical of pathogen infection (such as lipopolysaccharides that are found on bacteria and not in mammals), and produces inflammatory responses that either take care of the pathogen directly or bring in additional immune responses.  Several NLRP family members can form multiprotein complexes that activate caspases, now called inflammasomes.  NLRP3 is one of the best characterized of these, partly because mutations in components of the complex turn up in several human autoimmune diseases.  Most relevant for this story, NLRP3 is also thought to be involved in the response to inhaled silica or asbestos particles, and the uric acid crystals that are deposited in gout.  So, several apparently disparate diseases — gout, silicosis, asbestosis, and atherosclerosis — turn out to be the result of activating the same pathway in different places — in joints, the lung, or blood vessel walls.  And what activates the pathway doesn’t matter very much.  NLRP3 just doesn’t like crystals.

Are there other crystal-generated diseases out there to be discovered?  What would happen if we found a way to globally inhibit the inflammasome, would we cure all these diseases at once or cause other problems?  Can inflammasome activity be inhibited selectively in different cells?  Can you stop the crystals forming in the first place? These and other questions will probably keep pharmaceutical and biotech companies busy for years to come.

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