IL-1α facilitates the entry of immune cells into the brain during chronic Toxoplasma gondii infection

Abstract

Abstract Toxoplasma gondii is a parasite that causes chronic infections in the brain. Infection is asymptomatic in healthy hosts, but immunocompromised hosts experience severe disease in which fast-replicating parasites destroy brain tissue. Constant immune pressure is required to maintain control of the parasite, leading to the localized recruitment of immune cells. During chronic T. gondii infection, cell death occurs in focal areas of inflammation in the brain, suggesting the possibility of inflammatory molecule release. The alarmin IL-1α is expressed in the brain, and is upregulated by T. gondii infection. IL-1α is expressed by brain-resident microglia and infiltrating macrophages, implicating these cell types as sources of this cytokine. Mice lacking IL-1α or its receptor (IL-1R1), but not IL-1β, have defects in macrophage infiltration into the brain during chronic infection, as well as increased parasite burden in the brain. IL-1α has been the subject of less investigation than IL-1β, but may still rely on inflammatory cell death for its release. Indeed, this IL-1α-dependent immune response appears to be dependent on pyroptosis, as caspase-1/11−/− mice phenocopy IL-1R1−/− mice displaying decreased recruitment of myeloid cells into the brain and increased parasite burden. IL-1R1 is expressed on endothelial and other stromal cells in the brain vasculature, and IL-1R1−/− mice display decreased expression of the adhesion molecules ICAM-1 and VCAM-1 in the brain. These data suggest that during chronic T. gondii infection, IL-1α released from a macrophage population in the brain through pyroptosis acts on brain vasculature to modulate expression of adhesion molecules, facilitating the infiltration of monocytes to sites of infection.