IL-4Rα signaling by CD8α + dendritic cells contributes to cerebral malaria by enhancing inflammatory, Th1, and cytotoxic CD8 + T cell responses

J Biol Chem. Jan-Jun 2021;296:100615. doi: 10.1016/j.jbc.2021.100615. Epub 2021 Mar 30.

Abstract

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-4Rα only in CD8α+ DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared with WT mice, mice lacking IL-4Rα in CD11c+ or CD8α+ 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-4Rα signaling in CM pathogenesis that promotes CD8α+ DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8+ T cell responses.

Keywords: IL-4Rα; cerebral malaria; cytotoxic T cells; endothelial damage; infiltration to brain; inflammatory cytokines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Malaria, Cerebral / genetics
  • Malaria, Cerebral / immunology*
  • Malaria, Cerebral / pathology
  • Mice
  • Mice, Knockout
  • Plasmodium berghei / genetics
  • Plasmodium berghei / immunology*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th2 Cells / immunology
  • Th2 Cells / pathology

Substances

  • CD8 Antigens
  • CD8 antigen, alpha chain
  • Il4 protein, mouse
  • Il4ra protein, mouse
  • Receptors, Cell Surface
  • Interleukin-4