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25-Hydroxycholesterol suppresses interleukin-1–driven inflammation downstream of type I interferon

2014; American Association for the Advancement of Science; Volume: 345; Issue: 6197 Linguagem: Inglês

10.1126/science.1254790

1095-9203

Andrea Reboldi, Eric V. Dang, Jeffrey G. McDonald, Guosheng Liang, David W. Russell, Jason G. Cyster,

Systemic Lupus Erythematosus Research

Type I interferon (IFN) protects against viruses, yet it also has a poorly understood suppressive influence on inflammation. Here, we report that activated mouse macrophages lacking the IFN-stimulated gene cholesterol 25-hydroxylase (Ch25h) and that are unable to produce the oxysterol 25-hydroxycholesterol (25-HC) overproduce inflammatory interleukin-1 (IL-1) family cytokines. 25-HC acts by antagonizing sterol response element-binding protein (SREBP) processing to reduce Il1b transcription and to broadly repress IL-1-activating inflammasomes. In accord with these dual actions of 25-HC, Ch25h-deficient mice exhibit increased sensitivity to septic shock, exacerbated experimental autoimmune encephalomyelitis, and a stronger ability to repress bacterial growth. These findings identify an oxysterol, 25-HC, as a critical mediator in the negative-feedback pathway of IFN signaling on IL-1 family cytokine production and inflammasome activity.