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Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling

Drugs used to treat erectile dysfunction may be repurposed to inhibit inflammation and treat patients with sepsis. Taming TNF during sepsis The proinflammatory cytokine tumor necrosis factor (TNF) is required for an effective immune response to invading pathogens; however, excessive TNF signaling through its receptor TNFR leads to cell death and tissue damage, such as occurs during sepsis. The proteolytic shedding of TNFR from the cell surface decreases TNF signaling in cells and reduces TNF concentrations in the plasma. Deng et al. showed that treating mouse or human hepatocytes with the bacterial product LPS resulted in increased shedding of TNFR by the protease TACE, an event dependent on the second messenger cGMP. Treating mice that had sepsis with drugs that increased the plasma concentration of cGMP decreased inflammation and increased survival, suggesting that a similar strategy might provide a therapy against sepsis in humans. Proteolytic cleavage of the tumor necrosis factor (TNF) receptor (TNFR) from the cell surface contributes to anti-inflammatory responses and may be beneficial in reducing the excessive inflammation associated with multiple organ failure and mortality during sepsis. Using a clinically relevant mouse model of polymicrobial abdominal sepsis, we found that the production of inducible nitric oxide synthase (iNOS) in hepatocytes led to the cyclic guanosine monophosphate (cGMP)–dependent activation of the protease TACE (TNF-converting enzyme) and the shedding of TNFR. Furthermore, treating mice with a cGMP analog after the induction of sepsis increased TNFR shedding and decreased systemic inflammation. Similarly, increasing the abundance of cGMP with a clinically approved phosphodiesterase 5 inhibitor (sildenafil) also decreased markers of systemic inflammation, protected against organ injury, and increased circulating amounts of TNFR1 in mice with sepsis. We further confirmed that a similar iNOS-cGMP-TACE pathway was required for TNFR1 shedding by human hepatocytes in response to the bacterial product lipopolysaccharide. Our data suggest that increasing the bioavailability of cGMP might be beneficial in ameliorating the inflammation associated with sepsis.