Editors' ChoiceSepsis

HIF-1α at the center of the sepsis Yin and Yang

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Science Translational Medicine  25 Mar 2015:
Vol. 7, Issue 280, pp. 280ec50
DOI: 10.1126/scitranslmed.aaa9873

Ancient Chinese philosophy ascribes to two opposing but complementary forces found in all things in the universe: Yin, the confusion and turmoil; Yang, the peace and serenity. Similar opposing forces can be seen in sepsis, a major cause of death in the intensive care units that is characterized by a complex and dynamic but often dysregulated host inflammatory response to infection. Sepsis is a balance of pro- versus anti-inflammatory states, with an early cytokine inflammatory phase followed by a later immunosuppressive phase. Despite decades of investigation and numbers of failed trials, the underlying molecular and immunological basis for the sepsis is still not well understood.

Shalova and colleagues took a stab at understanding the mechanisms of sepsis by focusing on circulating blood monocytes. They compared the transcriptomes of monocytes from patients during Gram-negative sepsis to monocytes taken from the same patients after they have recovered weeks later. The monocytes shifted from a proinflammatory state during infection to a more immunosuppressed phenotype similar to control monocytes after sepsis resolved. The authors then profiled the transcriptomes of the same monocyte populations after stimulation with endotoxin ex vivo. Septic monocytes showed profound gene reprogramming with blunted response to endotoxin, including impaired NF-κB activation, whereas the recovered monocytes were fully capable of NF-κB signaling. Despite the defective response to endotoxin, the septic monocytes were still phagocytic and able to restrict bacterial growth, suggesting that these cells were not globally suppressed but rather reconfigured during sepsis. Importantly, at the center of this reconfiguration were upregulated hypoxia-inducible factor-1α (HIF-1α) and many hypoxia-inducible genes. HIF-1α triggered IRAKM, a negative regulator of Toll-like receptor signaling and inducer of endotoxin tolerance. Thus, HIF-1α may possibly control the transcriptional and functional re-programming of monocytes during sepsis

This work highlights the potential of HIF-1α as a possible pharmacologic target to modulate monocytic responses during sepsis. Continued system biology-based studies that combine serial patient samples, transcriptomic analyses, and functional studies, but focused on subpopulations of immune cells during the various phases of sepsis, will likely provide further insights into the complicated Yin and Yang responses during sepsis.

I. N. Shalova et al., Human monocytes undergo functional re-programing during sepsis mediated by hypoxia-inducible factor-1α. Immunity 42, 1-15 (2015). [Abstract]

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