IL-33 is required for a protective myeloid cell response to T. gondii infection in the brain

Abstract

Abstract Monocytes can traffic to the brain in response to a variety of CNS insults. During infection with the parasite Toxoplasma gondii, monocyte-derived myeloid cells cluster in areas of free parasite and are required to control infection. While the functions of these cells are being investigated, the mechanisms of their recruitment to the infected brain are largely unknown. In regions of focal inflammation, we observe a loss of brain-resident cells and hypothesize that damage to these cells is an initial step in monocyte recruitment. We are specifically exploring the alarmin IL-33 and its potential for immune amplification upon extracellular release. Although largely characterized in barrier tissues, IL-33 is expressed by oligodendrocytes in the CNS. We find that the absence of IL-33 signaling in infected mice results in decreased expression of ccl2, an important chemokine for monocyte recruitment. Using a CCL2-mcherry reporter mouse line we have visualized that CCL2 production greatly increases upon infection and occurs in areas of resident brain cell loss and inflammation. Aligning with a loss of ccl2 we see a decrease in the number of recruited macrophages in IL-33R knockout mice. Though IL-33 has been connected with Type 2 immune responses, IL-33R knockout mice exhibit functional defects in our model’s Th1-dominated environment of intracellular pathogen killing. Specifically, infiltrating myeloid cells in these mice have a decreased capacity to produce iNOS, which is critical for limiting parasite replication. Thus, infected mice lacking IL-33 signaling have an increase in brain tissue cyst numbers. Together, our results demonstrate the impact of one alarmin, IL-33, on monocyte recruitment and control of T. gondii CNS infection.