IL-17A activated by Toll-like receptor 9 contributes to the development of septic acute kidney injury

• Published in: American journal of physiology. Renal physiology Vol. 318; no. 1; pp. F238 - F247
• Main Authors: Naito, Yoshitaka, Tsuji, Takayuki, Nagata, Soichiro, Tsuji, Naoko, Fujikura, Tomoyuki, Ohashi, Naro, Kato, Akihiko, Miyajima, Hiroaki, Yasuda, Hideo
• Format: Journal Article
• Language: English
• Published: United States 01.01.2020
• Subjects: Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Apoptosis; Cytokines - metabolism; Dendritic Cells - metabolism; Disease Models, Animal; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukin-17 - pharmacology; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Mice; Mice, Knockout; Sepsis - metabolism; Sepsis - pathology; Spleen - metabolism; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - metabolism; interleukin-17A; acute kidney injury; Toll-like receptor 9; sepsis
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00313.2019

Toll-like receptor 9 (TLR9), which is activated by endogenously released mtDNA during sepsis, contributes to the development of polymicrobial septic acute kidney injury (AKI). However, downstream factors of TLR9 to AKI remain unknown. We hypothesized that IL-17A activated by TLR9 may play a critical role in septic AKI development. To determine the effects of TLR9 on IL-17A production in septic AKI, we used a cecal ligation and puncture (CLP) model in 9 knockout ( KO) mice and wild-type (WT) littermates. We also investigated the pathway from TLR9 activation in dendritic cells (DCs) to IL-17A production by γδT cells in vitro. To elucidate the effects of IL-17A on septic AKI, knockout ( KO) mice and WT littermates were subjected to CLP. We further investigated the relationship between the TLR9-IL-17A axis and septic AKI by intravenously administering recombinant IL-17A or vehicle into KO mice and assessing kidney function. IL-17A levels in both plasma and the peritoneal cavity and mRNA levels of IL-23 in the spleen were significantly higher in WT mice after CLP than in KO mice. Bone marrow-derived DCs activated by TLR9 induced IL-23 and consequently promoted IL-17A production in γδT cells in vitro. Knockout of improved survival, functional and morphological aspects of AKI, and splenic apoptosis after CLP. Exogenous IL-17A administration aggravated CLP-induced AKI attenuated by knockout of . TLR9 in DCs mediated IL-17A production in γδT cells during sepsis and contributed to the development of septic AKI.