Protective Role of MAVS Signaling for Murine Lipopolysaccharide-Induced Acute Kidney Injury

• Published in: ImmunoHorizons Vol. 8; no. 1; pp. 1 - 18
• Main Authors: Tran, Trang Anh Thi, Iwata, Yasunori, Hoang, Linh Thuy, Kitajima, Shinji, Yoneda-Nakagawa, Shiori, Oshima, Megumi, Sakai, Norihiko, Toyama, Tadashi, Yamamura, Yuta, Yamazaki, Hiroka, Hara, Akinori, Shimizu, Miho, Sako, Keisuke, Minami, Taichiro, Yuasa, Takahiro, Horikoshi, Keisuke, Hayashi, Daiki, Kajikawa, Sho, Wada, Takashi
• Format: Journal Article
• Language: English
• Published: United States 01.01.2024
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Animals; Humans; Lipopolysaccharides; Mice; Reactive Oxygen Species - metabolism; Sepsis - metabolism; Toll-Like Receptor 4 - metabolism
• ISSN: 2573-7732; 2573-7732
• DOI: 10.4049/immunohorizons.2300069

Despite treatment advances, acute kidney injury (AKI)-related mortality rates are still high in hospitalized adults, often due to sepsis. Sepsis and AKI could synergistically worsen the outcomes of critically ill patients. TLR4 signaling and mitochondrial antiviral signaling protein (MAVS) signaling are innate immune responses essential in kidney diseases, but their involvement in sepsis-associated AKI (SA-AKI) remains unclear. We studied the role of MAVS in kidney injury related to the TLR4 signaling pathway using a murine LPS-induced AKI model in wild-type and MAVS-knockout mice. We confirmed the importance of M1 macrophage in SA-AKI through in vivo assessment of inflammatory responses. The TLR4 signaling pathway was upregulated in activated bone marrow-derived macrophages, in which MAVS helped maintain the LPS-suppressed TLR4 mRNA level. MAVS regulated redox homeostasis via NADPH oxidase Nox2 and mitochondrial reverse electron transport in macrophages to alleviate the TLR4 signaling response to LPS. Hypoxia-inducible factor 1α (HIF-1α) and AP-1 were key regulators of TLR4 transcription and connected MAVS-dependent reactive oxygen species signaling with the TLR4 pathway. Inhibition of succinate dehydrogenase could partly reduce inflammation in LPS-treated bone marrow-derived macrophages without MAVS. These findings highlight the renoprotective role of MAVS in LPS-induced AKI by regulating reactive oxygen species generation-related genes and maintaining redox balance. Controlling redox homeostasis through MAVS signaling may be a promising therapy for SA-AKI.