Interleukin-17A released from intestinal γδT cells induces cytokine storm in mice with severe dengue

Abstract Blockade of TNF-α signaling protects mice from lethal infection with dengue virus (DENV); however, what causes cytokine storm or how TNF-α aggravates the disease remains unknown. Here, we performed transcriptome analysis of the liver and small intestine samples collected chronologically from DENV-3 P12/08-infected IFN-α/β and γ receptor knockout (IFN-α/β/γRKO) mice in the presence/absence of blockade of TNF-α Ab signaling. We found that TNF-α induced production of IL-17A by small intestinal γδT cells, regulated production of other cytokines such as IL-6 cooperatively with TNF-α, and played a crucial role in mortality. Also, neutrophil-derived matrix metalloprotease-8 was identified as an effector molecule causing vascular leakage. Blockade of TNF-α or IL-17A signaling strongly inhibited nuclear translocation of NF-κB p65 in stroma-like cells and epithelial cells, and prevented induction of IL-6. These findings enable us to better understand cytokine storm associated with severe dengue, and may facilitate development of new therapeutic strategies.