Altered X-chromosome inactivation predisposes to autoimmune manifestations in mice

Abstract

AbstractIn mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism that ensures the silencing of one X in females, may participate in these sex-biases. To test this hypothesis, we perturbed the expression of the trigger of XCI, the non-coding RNAXist.This resulted in exacerbated reactivation of X-linked genes of the Toll-like receptor 7 (TLR7) signalling pathway in monocyte/macrophages, dendritic cells and B cells during aging. Consequently, female mice spontaneously developed inflammatory signs similar, although milder, than those described in mouse models of lupus. Mechanistically, negative feedback ofTLR7signalling is impaired in macrophages with perturbed XCI, leading to delayed restoration of basal transcriptional levels of target genes upon stimulation. These observations support a direct link between the regulation of XCI and female-biased autoimmune manifestations and highlight altered XCI as a potential cause of autoimmunity.