IL-4 Treatment Mitigates Experimental Cerebral Malaria by Reducing Parasitemia, Dampening Inflammation, and Lessening the Cytotoxicity of T Cells
| Autor: | Ramesh P. Thylur, D. Channe Gowda, Christopher C. Norbury, Kishore Punnath, Kiran K. Dayanand, Xianzhu Wu |
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| Rok vydání: | 2021 |
| Předmět: |
Cytotoxicity
Immunologic Chemokine Plasmodium falciparum Immunology Malaria Cerebral Parasitemia Antimalarials Mice 03 medical and health sciences Chemokine receptor 0302 clinical medicine parasitic diseases Animals Humans Immunology and Allergy CXCL10 Medicine Cytotoxic T cell Plasmodium berghei Inflammation biology business.industry Brain biology.organism_classification medicine.disease Mice Inbred C57BL Cerebral Malaria Models Animal biology.protein Interleukin-4 business Signal Transduction T-Lymphocytes Cytotoxic 030215 immunology |
| Zdroj: | The Journal of Immunology. 206:118-131 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2000779 |
| Popis: | Cytokine responses to malaria play important roles in both protective immunity development and pathogenesis. Although the roles of cytokines such as TNF-α, IL-12, IFN-γ, and IL-10 in immunity and pathogenesis to the blood stage malaria are largely known, the role of IL-4 remains less understood. IL-4 targets many cell types and induces multiple effects, including cell proliferation, gene expression, protection from apoptosis, and immune regulation. Accordingly, IL-4 has been exploited as a therapeutic for several inflammatory diseases. Malaria caused by Plasmodium falciparum manifests in many organ-specific fatal pathologies, including cerebral malaria (CM), driven by a high parasite load, leading to parasite sequestration in organs and consequent excessive inflammatory responses and endothelial damage. We investigated the therapeutic potential of IL-4 against fatal malaria in Plasmodium berghei ANKA–infected C57BL/6J mice, an experimental CM model. IL-4 treatment significantly reduced parasitemia, CM pathology, and mortality. The therapeutic effect of IL-4 is mediated through multiple mechanisms, including enhanced parasite clearance mediated by upregulation of phagocytic receptors and increased IgM production, and decreased brain inflammatory responses, including reduced chemokine (CXCL10) production, reduced chemokine receptor (CXCR3) and adhesion molecule (LFA-1) expression by T cells, and downregulation of cytotoxic T cell lytic potential. IL-4 treatment markedly reduced the infiltration of CD8+ T cells and brain pathology. STAT6, PI3K–Akt–NF-κB, and Src signaling mediated the cellular and molecular events that contributed to the IL-4–dependent decrease in parasitemia. Overall, our results provide mechanistic insights into how IL-4 treatment mitigates experimental CM and have implications in developing treatment strategies for organ-specific fatal malaria. |
| Databáze: | OpenAIRE |
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