ena-STUDY-WASHINGTON UNIVERSITY  SCHOOL OF MEDICINE-15-10-2018-16:33:31:330-395
Select autophagy genes prevent hyper-inflammation by silencing microbiota dependent-macrophage homeostatic activation
Autophagy, a pathway for lysosomal degradation of cytosolic materials, is important for immunity. Autophagy genes can have roles independent of degradative autophagy pathway. Here we show that mice lacking certain autophagy genes in myeloid cells exhibited enhanced resistance to Listeria monocytogenes due to proinflammatory macrophage activation present prior to infection. Autophagy genes limited to the ULK and PI3K complexes involved in initiating autophagy, namely Beclin 1 and Fip200, but not genes in the ubiquitin-like conjugation systems of autophagy regulated basel activation of tissue-resident macrophages and resistance to Listeria. The activity of these genes in macrophages prevented hyper-inflammation by keeping phagocytes immunologically quiescent at baseline. Transcriptome and single-cell RNA sequencing revealed that macrophages in mice lacking Beclin 1 in myeloid cells exhibited elevated IFN? signaling. The hyper-inflammatory macrophage phenotype, as well as secondary effects on B and T cell phenotypes, was dependent on the presence of the IFN? receptor, but not on inflammasomes. IFN? driving the hyper-inflammatory state was derived from T cells with innate cells playing a minor role. We observed diminished basal macrophage activation in antibiotic treated wild-type mice but not mice lacking Beclin 1 in myeloid cells, establishing the dominance of autophagy gene regulation over effects of the microbiome in controlling the level of macrophage activation. These studies indicate that certain autophagy genes, but not the degradative autophagy pathway, are responsible for setting the level of myeloid cell activation in uninfected hosts dampening immune system activation in the host prior to challenge with an infecting agent.
Autophagy, a pathway for lysosomal degradation of cytosolic materials, is important for immunity. Autophagy genes can have roles independent of degradative autophagy pathway. Here we show that mice lacking certain autophagy genes in myeloid cells exhibited enhanced resistance to Listeria monocytogenes due to proinflammatory macrophage activation present prior to infection. Autophagy genes limited to the ULK and PI3K complexes involved in initiating autophagy, namely Beclin 1 and Fip200, but not genes in the ubiquitin-like conjugation systems of autophagy regulated basel activation of tissue-resident macrophages and resistance to Listeria. The activity of these genes in macrophages prevented hyper-inflammation by keeping phagocytes immunologically quiescent at baseline. Transcriptome and single-cell RNA sequencing revealed that macrophages in mice lacking Beclin 1 in myeloid cells exhibited elevated IFN? signaling. The hyper-inflammatory macrophage phenotype, as well as secondary effects on B and T cell phenotypes, was dependent on the presence of the IFN? receptor, but not on inflammasomes. IFN? driving the hyper-inflammatory state was derived from T cells with innate cells playing a minor role. We observed diminished basal macrophage activation in antibiotic treated wild-type mice but not mice lacking Beclin 1 in myeloid cells, establishing the dominance of autophagy gene regulation over effects of the microbiome in controlling the level of macrophage activation. These studies indicate that certain autophagy genes, but not the degradative autophagy pathway, are responsible for setting the level of myeloid cell activation in uninfected hosts dampening immune system activation in the host prior to challenge with an infecting agent.