Abstract
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 Toxoplasma gondii, 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-κB and inflammatory cytokine signatures overrepresented in blood-derived macrophages versus microglia. Interestingly, we also find that IL-1α is enriched in microglia and IL-1β in macrophages, which was also evident at the protein level. We find that mice lacking IL-1R1 or IL-1α, but not IL-1β, 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-1α ex vivo. Finally, using knockout mice as well as chemical inhibition, we show that ex vivo IL-1α 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 T. gondii infection, microglia specifically can release the alarmin IL-1α, a cytokine that promotes neuroinflammation and parasite control.
Footnotes
This work was funded by National Institutes of Health grants R01NS091067 and R56NS106028 to T.H.H., R01NS106383 to J.R.L., T32AI007046 to S.J.B., T32GM008328 to K.M.S., and T32AI007496 to C.A.O., as well as the Carter Immunology Center Collaborative Research Grant to T.H.H., The Alzheimer’s Association grant AARG-18-566113 to J.R.L., The Owens Family Foundation to J.R.L., and The University of Virginia R&D Award to J.R.L..