IL-4Rα signaling by CD8α+ dendritic cells contributes to cerebral malaria by enhancing inflammatory, Th1, and cytotoxic CD8+ T cell responses
Journal of Biological Chemistry(2021)
摘要
Persistent high levels of proinflammatory and Th1 responses contribute to cerebral malaria (CM). Suppression of inflammatory responses and promotion of Th2 responses prevent pathogenesis. IL-4 commonly promotes Th2 responses and inhibits inflammatory and Th1 responses. Therefore, IL-4 is widely considered as a beneficial cytokine via its Th2-promoting role that is predicted to provide protection against severe malaria by inhibiting inflammatory responses. However, IL-4 may also induce inflammatory responses, as the result of IL-4 action depends on the timing and levels of its production and the tissue environment in which it is produced. Recently, we showed that dendritic cells (DCs) produce IL-4 early during malaria infection in response to a parasite protein and that this IL-4 response may contribute to severe malaria. However, the mechanism by which IL-4 produced by DCs contributing to lethal malaria is unknown. Using Plasmodium berghei ANKA-infected C57BL/6 mice, a CM model, we show here that mice lacking IL-4R alpha only in CD8 alpha(+) DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared with WT mice, mice lacking IL-4R alpha in CD11c(+) or CD8 alpha(+) DCs showed reduced inflammatory responses leading to decreased Th1 and cytotoxic CD8(+) T cell responses, lower infiltration of CD8(+) T cells to the brain, and negligible brain pathology. The novel results presented here reveal a paradoxical role of IL-4R alpha signaling in CM pathogenesis that promotes CD8 alpha(+) DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8(+) T cell responses.
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关键词
IL-4Rα,inflammatory cytokines,cytotoxic T cells,infiltration to brain,endothelial damage,cerebral malaria
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