RESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Colchicina/farmacología , Citocinas/fisiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Células Mieloides/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antioxidantes/farmacología , Colchicina/farmacocinética , Simulación por Computador , Citocinas/biosíntesis , Factor 15 de Diferenciación de Crecimiento/genética , Hepatocitos/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Peritonitis/inducido químicamente , Peritonitis/prevención & control , Proteína Tirosina Fosfatasa no Receptora Tipo 6/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Metabolism is at the core of all biological functions. Anabolic metabolism uses building blocks that are either derived from nutrients or synthesized de novo to produce the biological infrastructure, whereas catabolic metabolism generates energy to fuel all biological processes. Distinct metabolic programs are required to support different biological functions. Thus, recent studies have revealed how signals regulating cell quiescence, proliferation, and differentiation also induce the appropriate metabolic programs. In particular, a wealth of new studies in the field of immunometabolism has unveiled many examples of the connection among metabolism, cell fate decisions, and organismal physiology. We discuss these findings under a unifying framework derived from the evolutionary and ecological principles of life history theory.