Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action. Weng et al. demonstrate that colchicine's well-known anti-inflammatory effects are not due its direct action on immune cells but are indirect effects, mediated by hepatokines such as GDF15, which are released as a result of colchicine action in the liver.

Automated summary

The study demonstrates that the anti-inflammatory effects of colchicine are mediated indirectly through the release of hepatokines such as GDF15, rather than through direct action on immune cells. This suggests that the efficacy and safety of colchicine depend on its selective action on hepatocytes, revealing a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may serve as useful pharmacodynamic biomarkers of colchicine action.