Assuntos
COVID-19 , RNA Viral , SARS-CoV-2 , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Humanos , RNA Viral/genética , RNA Viral/imunologia , COVID-19/imunologia , COVID-19/virologia , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Evasão da Resposta ImuneRESUMO
While pancreatic ß and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from ß cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that ß cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the ß cell glucose threshold and consequently lowers the glycaemic set point in vivo.
Assuntos
Ilhotas Pancreáticas , Células Secretoras de Somatostatina , Animais , Camundongos , Glucagon , Insulina , GlucoseRESUMO
Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.