| First Author | Wu X | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100615 | PubMed ID | 33798555 |
| Mgi Jnum | J:316348 | Mgi Id | MGI:6695659 |
| Doi | 10.1016/j.jbc.2021.100615 | Citation | Wu X, et al. (2021) IL-4Ralpha signaling by CD8alpha(+) dendritic cells contributes to cerebral malaria by enhancing inflammatory, Th1, and cytotoxic CD8(+) T cell responses. J Biol Chem :100615 |
| abstractText | 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 (Wu et al. (2018) J. Biol. Chem. 293, 10425-10434). However, the mechanism by which IL-4 produced by DCs contributing to lethal malaria is unknown. Using P. berghei ANKA-infected C57BL/6 mice, a CM model, we show here that mice lacking IL-4Ralpha only in CD8alpha(+) DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared to WT mice, mice lacking IL-4Ralpha in CD11c(+) or CD8alpha(+) 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-4Ralpha signaling in CM pathogenesis that promotes CD8alpha(+) DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8(+) T cell responses. |
