Inflammation, a physiological response to noxious stimuli of variable origin, is characterized by the expression and release of numerous cytokines, whose uncontrolled synthesis can rapidly lead to severe pathologies such as autoimmunity. Therefore, a tight regulation must be achieved in order to ensure, both temporally and spatially, accurate production of these molecules. Working in concert with regulatory proteins which have been described extensively, microRNAs appeared recently as novel actors in the network leading to an inflammatory context. To analyze globally the impact of miRNA on inflammatory responses of infectious origin, we performed viral inoculation in DICER-deficient mutant mice. In addition, using a genetic approach, in which a Dicer hypomorphic mutation was combined with the CD95 ^lpr/lpr allele, we investigated the consequences of low miRNA production on the initiation and development of lupus as a model of inflammatory settings triggered under sterile conditions. In this review, we discuss the data obtained with these two models within the frame of miRNA-dependent regulation of Type I Interferon-Stimulated genes.