DOKing TLR4 signals

The liver has a finite capacity for regeneration. In mice, removal of 70% of the liver (partial resection) is tolerated but 85% removal (massive resection) is often fatal. Cataldegirmen et al. show on page 473 that blocking RAGE (receptor for advanced glycation end products) allows massively resected mice to survive and regain liver function. Previous studies in mice suggested that recovery after partial resection requires an inflammatory stimulus—possibly provided by bacterial endotoxins, which are continuously filtered by the liver. This triggers activation of NFB in liver cells and production of the proregenerative cytokines TNF and interleukin 6 (IL-6), which are essential for hepatocyte proliferation. RAGE signaling is known to enhance chronic inflammation. The authors previously found that RAGE also promotes regeneration of injured nerves, which like liver regeneration requires inflammation. Cataldegirmen et al. now show that inflammation is also a good thing in the massively resected liver, but it is nevertheless suppressed by RAGE. The expression of RAGE was up-regulated on liver dendritic cells (DCs) after massive but not partial resection. RAGE signaling antagonized NFB activation in liver cells and decreased the production of TNF and IL-6. Blocking RAGE signaling, or expressing a mutant RAGE on DCs only, reversed the inhibition of inflammation and promoted liver regeneration. The mechanism behind the unusual antiinflammatory action of RAGE is not yet clear. Whatever the mechanism, the authors think that RAGE inhibition may be an effective way to enhance liver regeneration in humans.