Clues to psoriasis susceptibility
Nature Immunology
December 3, 2012
Why some individuals spontaneously develop psoriasis, a chronic inflammatory disease of the skin, is described in a paper published online this week in Nature Immunology.
Psoriatic skin lesions are infiltrated with abundant immune cells-including TH17 cells that secrete the proinflammatory mediators interleukin 17 (IL-17) and IL-22. While such a response helps to control microbial infections in the skin, in psoriasis this response is hyperactive and causes thickening of the epidermis and massive infiltration of neutrophils that release toxic mediators within the lesion.
Xiaoxia Li and colleagues report that the dysregulation of IL-17 signaling in TH17 cells contributes to disease. They use a disease model of psoriasis in mice harboring a specific mutation in Act1, protein that interacts with the IL-17 receptor and for which there is known mutation that is also associated with human disease.
Normally IL-17 signaling triggers a self-limiting inflammatory response, but Act1 mutant mice spontaneously develop chronic skin inflammation. The authors find mutant Act1 fails to associate with a chaperone protein hsp90, which would cease the inflammatory response. As a result, TH17 cells cannot turn off production of IL-22. The authors found that blocking IL-22 with neutralizing antibodies alleviated skin disease in the mutant mice. These findings suggest that anti-IL-22 therapies might be beneficial to those patients that express defective Act1.
doi: 10.1038/ni.2479
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