The mechanisms that regulate the transition between systemic inflammatory response syndrome (SIRS) and the endotoxin tolerance (ET) phase in sepsis are not yet clear. Now, Wilfred Jefferies and colleagues report that the ATP-binding cassette gene ABCF1 controls this transition by regulating innate immune responses in macrophages.
The researchers previously conducted a gene expression screen and identified ABCF1 as a potential regulator of immunity and inflammation. In their recent study, they show that ABCF1 is an E2 ubiquitin-conjugating enzyme that regulates macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype by promoting TLR4 endocytosis and activation of TRIF-dependent signalling. In a murine model of sepsis, ABCF1 haploinsufficiency led to increased expression of pro-inflammatory cytokines, failure to transition from SIRS to the ET phase, renal circulatory failure and increased mortality.
“During SIRS, the acute inflammatory response caused by pro-inflammatory cytokines damages the host tissue, which ultimately leads to death,” explains Jefferies. “Histological analysis of the ABCF1-deficient mice in the SIRS phase revealed widespread dilation and congestion of small vessels in the kidneys as well as a sludging effect of red blood cells being compacted together in these vessels. This form of vasculature dilation and congestion on a systemic scale results in a critical drop in blood pressure, which leads to insufficient delivery of blood and oxygen to central organs, including the brain and heart.”
The researchers conclude that ABCF1 modulates sepsis mortality by promoting transition to the ER phase, thereby repressing hypotension-induced renal circulatory failure. “As ABCF1 switches off pro-inflammatory pathways, our research may provide a map to explore new treatments for chronic and acute inflammatory diseases as well as autoimmune disorders,” says Jefferies.
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Arora, H. et al. The ATP-binding cassette gene ABCF1 functions as an E2 ubiquitin-conjugating enzyme controlling macrophage polarization to dampen lethal septic shock. Immunity 50, 418–431 (2019)
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Carney, E.F. ABCF1 switches off inflammation in sepsis. Nat Rev Nephrol 15, 255 (2019). https://doi.org/10.1038/s41581-019-0136-5
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DOI: https://doi.org/10.1038/s41581-019-0136-5