The damage signal IL-33 facilitates focal immune responses to Toxoplasma gondii in the brain

• Published in: The Journal of immunology (1950) 2018-05, Vol.200 (1_Supplement), p.43-43.4
• Main Authors: Still, Katherine M., Thompson, Jeremy, Batista, Samantha, Hayes, Nikolas, Harris, Tajie H.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.43.4

An intact immune system is critical for survival of hosts chronically infected with T. gondii. We observe clusters of immune cells surrounding regions of free parasite within brain tissue. Many of these cells are monocyte-derived and have parasite-limiting capacity, but the initial cues which instruct their proximity to parasite are not well understood. One potential mechanism of broad relevance is the incitement of damage. We explored the importance of IL-33, a protein released upon cell damage, in the recruitment of monocytes in our model. We found IL-33 to be expressed by oligodendrocytes during T. gondii infection, and observed regions of oligodendrocyte loss in infected mouse and human brain tissue, implying ample opportunity for IL-33 release. Upon infection, induction of the monocyte chemoattractant, CCL2, was dependent on IL-33 signaling, as visualized using CCL2-mcherry reporter mice. CCL2 signal was focal and expressed by astrocytes surrounding immune cell foci. The concept that IL-33 could be acting on astrocytes directly was supported by bone marrow chimeras which implicated a radio-resistant responder to IL-33. In alignment with CCL2 induction, IL-33 was required for infiltration of monocyte-derived myeloid cells, and expansion of focal myeloid cell-derived iNOS, an anti-parasitic mechanism crucial for survival during chronic infection. Consequently, intact IL-33 signaling was necessary for control of brain parasite burden. These results expand our knowledge of alarmin signaling in the brain, an environment which is likely unique to the periphery in immune response initiation due to the structural challenge of the BBB, and demonstrate the importance of one damage signal in focal control of T. gondii infection.