| Popis: |
SUMMARY An intact immune response is critical for survival of hosts chronically infected with Toxoplasma gondii . We observe clusters of macrophages surrounding replicating parasite in brain tissue, but the initial cues which instruct focal inflammatory reactions in the central nervous system (CNS) are not well understood. One potential mechanism of broad relevance is host cell damage. Here we find that IL-33, a nuclear alarmin, is critical for control of T. gondii parasites in the brain. IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, and a loss of nuclear IL-33 staining is observed in association with replicating T. gondii in infected mouse and human brain tissue, suggestive of IL-33 release. IL-33 signaling is required for induction of chemokines in astrocytes, including focal CCL2 production as visualized using CCL2-mCherry reporter mice. Bone marrow chimera experiments support the hypothesis that IL-33 could be acting directly on astrocytes, as the relevant IL-33-responding cell is radio-resistant. In alignment with CCL2 induction, IL-33 signaling is required for the infiltration of CCR2 + myeloid cells that express anti-parasitic iNOS locally. These results expand our knowledge of alarmin signaling in the brain, an environment which is unique from the periphery and demonstrates the importance of a single damage signal in focal control of T. gondii infection in the CNS. |
