Ibudilast Attenuates Folic Acid–Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways

Abstract

Folic acid (FA)-induced renal tubule damage, which is characterized by extensive inflammation, is a common model of acute kidney injury (AKI). Pyroptosis, a pro-inflammatory form of cell death due to the activation of inflammatory caspases, is involved in AKI progression. Ibudilast, a TLR4 antagonist, has been used in the clinic to exert an anti-inflammatory effect on asthma. However, researchers have not explored whether ibudilast exerts a protective effect on AKI by inhibiting inflammation. In the present study, ibudilast reversed FA-induced AKI in mice, as indicated by the reduced serum creatinine and urea nitrogen levels, and improved renal pathology, as well as the downregulation of kidney injury marker-1. In addition, ibudilast significantly increased the production of the anti-inflammatory factor IL-10 while suppressing the secretion of the pro-inflammatory cytokine TNF-α and macrophage infiltration. Moreover, in the injured kidney, ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL1-β, IL-18, and GSDMD cleavage), and decreased the number of TUNEL-positive cells. Further mechanistic studies showed that ibudilast administration inhibited the FA-induced upregulation of TLR4, blocked NF-κB nuclear translocation, and reduced the phosphorylation of NF-κB and IκBα, p38, ERK, and JNK. Thus, this study substantiates the protective effect of ibudilast on FA-induced AKI in mice and suggests that protection might be achieved by reducing pyroptosis and inflammation, likely through the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways.

Macrophage-biomimetic porous Se@SiO2 nanocomposites for dual modal immunotherapy against inflammatory osteolysis

“…LPS stimulation promotes M1 polarization via the TLR4 pathway. Generally, TLR4 mediates LPS stimulation downstream of the MAPK and NF-κB signaling pathways [ 46 ]. The NF-κB pathway is important in macrophage polarization.…”

Identification of cross-talk pathways and ferroptosis-related genes in periodontitis and type 2 diabetes mellitus by bioinformatics analysis and experimental validation

“…Ibudilast is a safe orally-available phosphodiesterase 4 inhibitor that has been used in clinical practice for over 20 years. It inhibits the production of proinflammatory factors and the Th17 response in vivo to exert anti-inflammatory effects ( 65 , 66 ). Ibudilast can be used to treat acute kidney injury and rheumatoid arthritis in animal models ( 67 ).…”

Conciliatory Anti-Allergic Decoction Attenuates Pyroptosis in RSV-Infected Asthmatic Mice and Lipopolysaccharide (LPS)-Induced 16HBE Cells by Inhibiting TLR3/NLRP3/NF-κB/IRF3 Signaling Pathway

“…NLRP3 inflammasome activation results in Caspase 1-dependent release of the IL-1β and IL-18, and the gasdermin D-mediated pyroptotic cell death [41]. Studies have suggested that pyroptosis is closely participated in the pathogenesis of many diseases, including asthma [10,42], acute kidney injury [43], and depression 13 Journal of Immunology Research [44]. Besides, we also investigated the changes of pyroptosis in OVA-induced asthma mice with RSV infection and LPSinduced 16HBE cells.…”