MicroRNA‐155 potentiates the inflammatory response in hypothermia by suppressing IL‐10 production

Abstract

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.

Suppression of Transforming Growth Factor β Receptor 2 and Smad5 Is Associated with High Levels of MicroRNA miR-155 in the Oral Mucosa during Chronic Simian Immunodeficiency Virus Infection

“…A number of these small RNAs have been implicated in mediating inflammation (36,37), and miR-155 levels were shown to be upregulated during inflammatory responses (38, 39). Billeter et al (40) showed that miR-155 played a role in potentiating inflammatory responses. Other studies have shown that miR-155 expression is induced in response to the presence of inflammatory stimuli or activation of Toll-like receptors (TLR) or cytokine stimulation (38,41) and plays a role in regulating germinal center responses (42,43).…”

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling

“…Further, proinflammatory effects of microRNA-155 were observed in monocytes. Transfection of monocyte cultures with microRNA-155 mimic led to increased proinflammatory cytokine and chemokine production and expression of the chemokine receptor CCR7, whereas IL-10 secretion and CCR2 expression were decreased [13,14]. These effects of microRNA-155 in monocytes and macrophages were attributed, at least in part, to a decreased repression of the suppressor of cytokine signaling-1 and SH2-containing inositol-5′-phosphatase 1, potent inhibitors of inflammation [5,6,13].…”

Mammalian microRNAs and long noncoding RNAs in the host-bacterial pathogen crosstalk

“…The involvement of this miRNA in the proinflammatory response has been thoroughly investigated: among others, miR-155 targets SHIP1 (Fig 2c), a negative regulator of the NF-κB pathway [35,36], and SOCS1 (suppressor of cytokine signalling 1), an effector involved in the homeostasis of Treg cells [37]. This in turn, stimulates the expression of the proinflammatory cytokines TNF-α, IL-6, IL-1β, IL-8 and IL-12, while it reduces the expression of the anti-inflammatory cytokine IL-10 [38,39]. A complex interplay occurs upon infection, as IL-10 itself can reduce miR-155 expression in response to LPS [40].…”