Gasdermin-D-dependent IL-1 α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection

Microglia, the resident immune cells of the brain parenchyma, are thought to be first-line defenders against CNS infections. We sought to identify specific roles of microglia in the control of the eukaryotic parasite , an opportunistic infection that can cause severe neurological disease. In order to identify the specific function of microglia in the brain during infection, we sorted microglia and infiltrating myeloid cells from infected microglia reporter mice. Using RNA-sequencing, we find strong NF-B and inflammatory cytokine signatures overrepresented in blood-derived macrophages versus microglia. Interestingly, we also find that IL-1 is enriched in microglia and IL-1 in macrophages, which was also evident at the protein level. We find that mice lacking IL-1R1 or IL-1, but not IL-1, have impaired parasite control and immune cell infiltration specifically within the brain. Further, by sorting purified populations from infected brains, we show that microglia, not peripheral myeloid cells, release IL-1. Finally, using knockout mice as well as chemical inhibition, we show that IL-1 release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in immune infiltration into the brain and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic infection, microglia specifically can release the alarmin IL-1, a cytokine that promotes neuroinflammation and parasite control.