Silicosis A couple of years ago, Jurg Tschopp’s group showed that uric acid crystals acted as inflammatory agents (and probably, also as adjuvants) by stimulating the Nalp3 inflammasome.1 A month ago, Richard Flavell’s group showed that alum adjuvant — also (sort of) crystalline — also acts through the Nalp3 inflammasome.2 And now, a paper just out in PNAS says that crystalline silica causes silicosis by acting through, you’ll never guess, the Nalp3 inflammasome. 3 Could a trend be showing up?

I don’t know much about silicosis, other than the obvious stuff (it’s an inflammatory lung disease caused by inhaling crystalline silica) and to be honest I had never much wondered why silica would cause lung disease; I assumed that it’s toxic, caused cell damage because of direct cytotoxicty, and the cell damage led to an inflammatory response. It turns out that that’s partly right; silica is cytotoxic and does cause cell damage, but the cell damage per se is not the cause of the inflammation, because Nalp3-knockout mice still had the same amount of cell death, but didn’t have the inflammation.

Nalp3 is an intracellular sensor, which raises an obvious question4 about all these crystals: How do they get into the cell to stimulate the response? As far as I know, this is the first of the papers to look at this question, and the answer is a little disappointing in that it seems fairly simple: It’s just endocytosis.

… endocytosis of silica by macrophages is needed to activate the Nalp3 inflammasome in response to silica for the resultant processing and secretion of proinflammatory cytokines.

Silicosis (Wellcome Images)I was at least half expecting a much more complicated and exciting answer, but this does make sense.  (I don’t know, actually, if silica, alum, and uric acid crystals are about the same size, or if for some other reason endocytosis is not a plausible explanation for the other two.)  That still leaves the issue of how the crystals get out of the endosome and into the cytosol, but we do know that in macrophages and dendritic cells there’s a poorly-characterized pathway by which some substances — proteins that are cross-presented, in particular — can exit the endosome and gain access to the cytosol, so we’re not adding any new mysteries, anyway.

The next candidate is probably asbestos; at this point, I think it’s fairly likely that asbestosis is also mediated by the Nalp3 inflammasome.

The only one of these crystalline substances that’s physiological is uric acid — monosodium urate crystals, a natural adjuvant that’s believed to act as a danger signal for cell death. I wonder if all these things are mimicking MSU crystals, or if there’s some other reason they act through the same receptor.

  1. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. 440, 237 – 241 (11 Jan 2006), doi:10.1038/nature04516[]
  2. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature  453, 1122-1126 doi:10.1038/nature06939[]
  3. Cassel, S.L., Eisenbarth, S.C., Iyer, S.S., Sadler, J.J., Colegio, O.R., Tephly, L.A., Carter, A.B., Rothman, P.B., Flavell, R.A., Sutterwala, F.S. (2008). The Nalp3 inflammasome is essential for the development of silicosis. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0803933105[]
  4. Brought up by Kay, last time I talked about it[]