RESUMO
Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.
Assuntos
Antígenos CD11 , Colite , Exossomos , Inflamação , Células Mieloides , Animais , Antígenos CD11/genética , Antígenos CD11/imunologia , Colite/genética , Colite/imunologia , Exossomos/genética , Exossomos/imunologia , Inflamação/genética , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Intestinos/imunologia , Lipídeos , Mamíferos/genética , Mamíferos/imunologia , Camundongos , MicroRNAs/imunologia , Proteínas Monoméricas de Ligação ao GTP/imunologia , Células Mieloides/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator 6 Associado a Receptor de TNF/imunologiaRESUMO
A retrospective review of 10 infected median sternotomies revealed that the management may be difficult and several procedures may be required to obtain a satisfactory result. Repeated curettage was successful in four patients. The cavity created by d ebridement was treated by the temporary insertion of gentamicin beads in one patient and by the Papineau bone grafting procedure in two. In two patients the thoracic cage became unstable as a result of extensive d ebridement and was stabilized successfully by inserting Harrington compression rods. One patient died of mediastinitis.