REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kB activation

Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-kB (NF-kB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1^+/2 macrophages. REDD-1 overexpression stimulated NF-kB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-kB activation was independent of 2 classic IKK-dependent NF-kB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IkBa, to elicit atypical NF-kB activation during the delayed and persistent phases of inflammation after stimulation. Moreover, REDD-1 knockdown mitigated vascular inflammation and permeability in endotoxemic mice, resulting in decreases in immune cell infiltration, systemic inflammation, caspase-3 activation, apoptosis, and consequent mortality. We further confirmed the inflammatory and cytotoxic effects of REDD-1 in endotoxemic REDD-1^+/2 mice. Our data support the likelihood that REDD-1 exacerbates endotoxemic inflammation via atypical NF-kB activation by sequestering IkBa.