Abstract
Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF-κB and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1β in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1β, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, 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 brain inflammation and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.
Highlights
Microglia, resident immune cells of the CNS, are thought to defend against infections
IFN-γ acts on target cells to induce an anti-parasitic state, allowing for the destruction of the parasite through a number of mechanisms including the recruitment of immunity-related GTPases (IRGs) and guanylate binding proteins (GBPs) to the parasitophorous vacuole, as well as the production of nitric oxide (NO)[20,21,22,23,24,25]
We propose that one specific function of microglia during T. gondii infection is to release the alarmin IL-1α to promote neuroinflammation and parasite control
Summary
Resident immune cells of the CNS, are thought to defend against infections. 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 brain inflammation and parasite control These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control. Whole-brain RNA-sequencing has shown that infected mice differ in gene expression from uninfected mice, and exhibit enrichment for immune and inflammation-related pathways[8] Brain resident cells such as astrocytes have been demonstrated to produce chemokines and cytokines in the brain that promote inflammation and parasite control, as well as to be able to directly kill parasites in vitro[9,10,11,12,13,14,15,16]. The role of IL-1 signaling in the brain during chronic infection has not been addressed
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