Therapeutic hypothermia is commonly used to improve neurological outcomes in patients after
cardiac arrest. However,
therapeutic hypothermia increases
sepsis risk and unintentional
hypothermia in surgical patients increases infectious complications. Nonetheless, the molecular mechanisms by which
hypothermia dysregulates innate immunity are incompletely understood. We found that exposure of human monocytes to cold (32°C) potentiated LPS-induced production of TNF and
IL-6, while blunting
IL-10 production. This dysregulation was associated with increased expression of microRNA-155 (miR-155), which potentiates
Toll-like receptor (TLR) signaling by negatively regulating Ship1 and Socs1. Indeed, Ship1 and Socs1 were suppressed at 32°C and miR-155
antagomirs increased Ship1 and Socs1 and reversed the alterations in
cytokine production in cold-exposed monocytes. In contrast, miR-155 mimics phenocopied the effects of cold exposure, reducing Ship1 and Socs1 and altering TNF and
IL-10 production. In a murine model of LPS-induced
peritonitis, cold exposure potentiated
hypothermia and decreased survival (10 vs. 50%; P < 0.05), effects that were associated with increased miR-155, suppression of Ship1 and Socs1, and alterations in TNF and
IL-10. Importantly, miR-155-deficiency reduced
hypothermia and improved survival (78 vs. 32%, P < 0.05), which was associated with increased Ship1, Socs1, and
IL-10. These results establish a causal role of miR-155 in the dysregulation of the inflammatory response to
hypothermia.