RESUMEN
The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.
Asunto(s)
Colangitis Esclerosante , Microbioma Gastrointestinal , Inflamación , Hígado , Macrófagos , Enfermedad del Hígado Graso no Alcohólico , Simbiosis , Animales , Femenino , Humanos , Masculino , Ratones , Bacteroidetes/metabolismo , Colangitis Esclerosante/inmunología , Colangitis Esclerosante/microbiología , Colangitis Esclerosante/patología , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Perfilación de la Expresión Génica , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Hígado/inmunología , Hígado/patología , Hígado/microbiología , Macrófagos/citología , Macrófagos/inmunología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/patología , Vena Porta , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/metabolismo , Análisis de la Célula Individual , Simbiosis/inmunologíaRESUMEN
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.