Correspondence

The Danger Within

N Engl J Med 2004; 350:2721-2722June 24, 2004

Article

To the Editor:

Jerome and Corey (Jan. 22 issue)1 comment on the identification of urate crystals as an immunologic danger signal released from apoptotic cells in mice, as shown in part by the ability of purified urate crystals to induce maturation of dendritic cells in vitro (when cultured in 10 percent fetal-calf serum).2 Inconsistent with this proposed signal is the finding that humans lacking xanthine oxidase, and hence urate, have no known immunologic disorder.3 Because mice and cattle (but not humans) express urate oxidase (uricase), we wondered whether the hydrogen peroxide produced by uricase in fetal-calf serum might be responsible for effects attributed to urate crystals. Urate crystals induced maturation of dendritic cells that were cultured in fetal-calf serum, but not those cultured in human serum. Incubating dendritic cells with urate crystals in fetal-calf serum, but not in human serum, resulted in the production of reactive oxygen species. Adding hydrogen peroxide alone or urate crystals and uricase in combination (but neither alone) induced maturation of dendritic cells in human serum. In humans lacking uricase, the mitochondria of apoptotic cells produce abundant reactive oxygen species. Our results suggest that the reactive oxygen species, rather than the uric acid, may be the ultimate danger signal.

Yiing Gu, Ph.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
ac@sickkids.ca

Michael S. Hershfield, M.D.
Duke University Medical Center, Durham, NC 27710

Amos Cohen, Ph.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

3 References

1. 1

   Jerome KR, Corey L. The danger within. N Engl J Med 2004;350:411-412
   Full Text | Web of Science | Medline

2. 2

   Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516-521
   CrossRef | Web of Science | Medline

3. 3

   Ichida K, Amaya Y, Kamatani N, Nishino T, Hosoya T, Sakai O. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J Clin Invest 1997;99:2391-2397
   CrossRef | Web of Science | Medline

Author/Editor Response

The study by Shi et al.1 left open the question of how urate crystals are recognized by dendritic cells. The data presented by Gu et al. suggest that it is not the urate crystals themselves that are recognized but, instead, the hydrogen peroxide produced when urate is degraded by urate oxidase (uricase). Because mice express urate oxidase, hydrogen peroxide may be the murine “ultimate danger signal.” However, some questions remain. Is the effect specific to hydrogen peroxide, or do other reactive oxygen species such as hydroxyl or superoxide suffice? Is there a role for catalase and glutathione peroxidase, which rapidly degrade hydrogen peroxide? Knockout mice lacking xanthine oxidase have been generated (but they are “runted” and die by six weeks of age)2; do they lack the ability to respond to danger signals? Can human cells respond to urate crystals? Can such cells respond to reactive oxygen species, or was this pathway sacrificed when xanthine oxidase expression was lost? All these questions can be approached experimentally. We look forward to the answers and suspect that further complexity awaits.

Keith R. Jerome, M.D., Ph.D.
Lawrence Corey, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109

2 References

1. 1

   Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516-521
   CrossRef | Web of Science | Medline

2. 2

   Vorbach C, Scriven A, Capecchi MR. The housekeeping gene xanthine oxidoreductase is necessary for milk fat droplet enveloping and secretion: gene sharing in the lactating mammary gland. Genes Dev 2002;16:3223-3235
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Karina Ckless, Samantha R. Hodgkins, Jennifer L. Ather, Rebecca Martin, Matthew E. Poynter. (2011) Epithelial, dendritic, and CD4+ T cell regulation of and by reactive oxygen and nitrogen species in allergic sensitization. Biochimica et Biophysica Acta (BBA) - General Subjects 1810:11, 1025-1034
   CrossRef

2. 2

   Asis Palazón, Juan Dubrot, Iván Martinez-Forero, Ana Rouzaut-Subirá, Carmen Ochoa, José Luis Perez-Gracia, Sandra Hervás-Stubbs, Ignacio Melero. (2008) Polly Matzinger's “danger model” finds its predicted danger-denoting self moieties. Inmunología 27:4, 205-211
   CrossRef