TY - JOUR
T1 - IL-4Rα signaling by CD8α+ dendritic cells contributes to cerebral malaria by enhancing inflammatory, Th1, and cytotoxic CD8+ T cell responses
AU - Wu, Xianzhu
AU - Brombacher, Frank
AU - Chroneos, Zissis C.
AU - Norbury, Christopher C.
AU - Gowda, D. Channe
N1 - Funding Information:
We thank Dr Ajay Chawla, University of California, San Francisco, and Dr Finkelman, University of Cincinnati College of Medicine, who respectively provided us IL-4Rαfl/fl mice and IL-4Rα−/− mice in C57BL/6 background. We also thank MR4/ BeiResources (Manassas, VA) for providing P. berghei ANKA strain. -This work was funded in parts by the grant R01 AI41139 from the National Institute of Allergy and Infectious Diseases, NIH, and the grant with the Pennsylvania Department of Health using Tobacco CURE Funds SAP# 4100083097 (D. C. G. and C. C. N.). The Pennsylvania Department of Health specifically disclaims responsibility for any analysis, interpretations, or conclusions. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
Funding and additional information—This work was funded in parts by the grant R01 AI41139 from the National Institute of Allergy and Infectious Diseases, NIH, and the grant with the Pennsylvania Department of Health using Tobacco CURE Funds SAP# 4100083097 (D. C. G. and C. C. N.). The Pennsylvania Department of Health specifically disclaims responsibility for any analysis, interpretations, or conclusions. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jbc.2021.100615
DO - 10.1016/j.jbc.2021.100615
M3 - Article
C2 - 33798555
AN - SCOPUS:85105254768
VL - 296
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
M1 - 100615
ER -