RESUMEN
BACKGROUND & AIMS: Liver CRIg+ (complement receptor of the immunoglobulin superfamily) macrophages play a critical role in filtering bacteria and their products from circulation. Translocation of microbiota-derived products from an impaired gut barrier contributes to the development of obesity-associated tissue inflammation and insulin resistance. However, the critical role of CRIg+ macrophages in clearing microbiota-derived products from the bloodstream in the context of obesity is largely unknown. METHODS: We performed studies with CRIg-/-, C3-/-, cGAS-/-, and their wild-type littermate mice. The CRIg+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut microbial DNA-containing extracellular vesicles (mEVs) were adoptively transferred into CRIg-/-, C3-/-, or wild-type mice, and tissue inflammation and insulin sensitivity were measured in these mice. After coculture with gut mEVs, cellular insulin responses and cGAS/STING-mediated inflammatory responses were evaluated. RESULTS: Gut mEVs can reach metabolic tissues in obesity. Liver CRIg+ macrophages efficiently clear mEVs from the bloodstream through a C3-dependent opsonization mechanism, whereas obesity elicits a marked reduction in the CRIg+ macrophage population. Depletion of CRIg+ cells results in the spread of mEVs into distant metabolic tissues, subsequently exacerbating tissue inflammation and metabolic disorders. Additionally, in vitro treatment of obese mEVs directly triggers inflammation and insulin resistance of insulin target cells. Depletion of microbial DNA blunts the pathogenic effects of intestinal EVs. Furthermore, the cGAS/STING pathway is crucial for microbial DNA-mediated inflammatory responses. CONCLUSIONS: Deficiency of CRIg+ macrophages and leakage of intestinal EVs containing microbial DNA contribute to the development of obesity-associated tissue inflammation and metabolic diseases.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Hepatitis/inmunología , Resistencia a la Insulina/inmunología , Macrófagos del Hígado/inmunología , Obesidad/complicaciones , Animales , Complemento C3/genética , ADN Bacteriano/inmunología , ADN Bacteriano/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Microbioma Gastrointestinal/genética , Hepatitis/microbiología , Hepatitis/patología , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Macrófagos del Hígado/metabolismo , Hígado/citología , Hígado/inmunología , Hígado/patología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Nucleotidiltransferasas/metabolismo , Obesidad/sangre , Obesidad/inmunología , Receptores de Complemento/metabolismo , Transducción de Señal/inmunologíaRESUMEN
Various microbial products leaked from gut lumen exacerbate tissue inflammation and metabolic disorders in obesity. Vsig4+ macrophages are key players preventing infiltration of bacteria and their products into host tissues. However, roles of islet Vsig4+ macrophages in the communication between microbiota and ß cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in ß cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into ß cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into ß cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in ß cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in ß cells and subsequently obesity-associated islet abnormalities.
Asunto(s)
ADN Bacteriano/metabolismo , Inflamación/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Obesidad/metabolismo , Animales , ADN Bacteriano/sangre , ADN Bacteriano/genética , Dieta Alta en Grasa/efectos adversos , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Microbioma Gastrointestinal/genética , Humanos , Inflamación/etiología , Inflamación/genética , Secreción de Insulina , Islotes Pancreáticos/patología , Macrófagos/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Obesidad/genética , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Transducción de Señal/genéticaRESUMEN
Insulin resistance is a major pathophysiologic defect in type 2 diabetes and obesity, while anti-inflammatory M2-like macrophages are important in maintaining normal metabolic homeostasis. Here, we show that M2 polarized bone marrow-derived macrophages (BMDMs) secrete miRNA-containing exosomes (Exos), which improve glucose tolerance and insulin sensitivity when given to obese mice. Depletion of their miRNA cargo blocks the ability of M2 BMDM Exos to enhance insulin sensitivity. We found that miR-690 is highly expressed in M2 BMDM Exos and functions as an insulin sensitizer both in vivo and in vitro. Expressing an miR-690 mimic in miRNA-depleted BMDMs generates Exos that recapitulate the effects of M2 BMDM Exos on metabolic phenotypes. Nadk is a bona fide target mRNA of miR-690, and Nadk plays a role in modulating macrophage inflammation and insulin signaling. Taken together, these data suggest miR-690 could be a new therapeutic insulin-sensitizing agent for metabolic disease.