RESUMO
Proven roles for hemocytes (blood cells) have expanded beyond the control of infections in Drosophila. Despite this, the crucial role of hemocytes in post-embryonic development has long thought to be limited to control of microorganisms during metamorphosis. This has previously been shown by rescue of adult development in hemocyte-ablation models under germ-free conditions. Here, we show that hemocytes have an essential role in post-embryonic development beyond their ability to control the microbiota. Using a newly generated strong hemocyte-specific driver line for the GAL4/UAS system, we show that specific ablation of hemocytes is early pupal lethal, even under axenic conditions. Genetic rescue experiments prove that this is a hemocyte-specific phenomenon. RNA-seq data suggests that dysregulation of the midgut is a prominent consequence of hemocyte ablation in larval stages, resulting in reduced gut lengths. Dissection suggests that multiple processes may be affected during metamorphosis. We believe this previously unreported role for hemocytes during metamorphosis is a major finding for the field.
Assuntos
Proteínas de Drosophila , Microbiota , Animais , Drosophila , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Desenvolvimento Embrionário , Hemócitos , LarvaRESUMO
Neutrophil extracellular traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation, and activate myeloid cells to produce type I interferons (IFNs), proinflammatory cytokines that regulate the immune system. Here, we showed that macrophages and other myeloid cells phagocytosed NETs. Once in phagosomes, NETs translocated to the cytosol, where the DNA backbones of these structures activated the innate immune sensor cyclic GMP-AMP synthase (cGAS) and induced type I IFN production. The NET-associated serine protease neutrophil elastase (NE) mediated the activation of this pathway. We showed that NET induction in mice treated with the lectin concanavalin A, a model of autoimmune hepatitis, resulted in cGAS-dependent stimulation of an IFN response, suggesting that NETs activated cGAS in vivo. Thus, our findings suggest that cGAS is a sensor of NETs, mediating immune cell activation during infection.
Assuntos
Armadilhas Extracelulares , Animais , Citosol , DNA , Camundongos , Neutrófilos , Nucleotidiltransferases/genéticaRESUMO
Neutrophils are important innate immune cells that tackle invading pathogens with different effector mechanisms. They acquire this antimicrobial potential during their maturation in the bone marrow, where they differentiate from hematopoietic stem cells in a process called granulopoiesis. Mature neutrophils are terminally differentiated and short-lived with a high turnover rate. Here, we show a critical role for linker histone H1 on the differentiation and function of neutrophils using a genome-wide CRISPR/Cas9 screen in the human cell line PLB-985. We systematically disrupted expression of somatic H1 subtypes to show that individual H1 subtypes affect PLB-985 maturation in opposite ways. Loss of H1.2 and H1.4 induced an eosinophil-like transcriptional program, thereby negatively regulating the differentiation into the neutrophil lineage. Importantly, H1 subtypes also affect neutrophil differentiation and the eosinophil-directed bias of murine bone marrow stem cells, demonstrating an unexpected subtype-specific role for H1 in granulopoiesis.