PMC10410139_01
Mitochondrial damage-associated molecular patterns (DAMPs) disturb podocyte innate immunity pathways. Mitochondrial DAMPS such as mitochondrial DNA (mtDNA), mitochondrial RNA (mtRNA), cytochrome C (Cyt C), and reactive oxygen species (ROS) contribute to disturbance in podocyte homeostasis via activation of various DNA/RNA-sensing and inflammasome pathways leading to inflammation, immune system activation and different types of cell death including apoptosis, ferroptosis and pyroptosis. Therefore, targeting immune markers such as toll-like receptors (TLRs), tumor necrosis factor alpha (TNFalpha), NLR family pyrin domain containing 3 (NLRP3), retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), mitochondrial antiviral-signaling protein (MAVS), absent in melanoma 2 (AIM2), stimulator of interferon gene (STING), and/or myeloid differentiation primary response 88 (MyD88) may represent future therapeutic approaches to treat FSGS. AIM2 - absent in melanoma 2; APAF1, apoptotic pepdidase activating factor 1; BAK, Bcl2 homologous antagonist/killer; BAX, Bcl2-associated X protein; CASP1, caspase 1; CASP3, caspase 3; CASP9, caspase 9; cGAS, cyclic GMP-AMP synthase; cGAMP, 2'3'-cyclic GMP-AMP; Cyt C, cytochrome c; ETC, electron transport chain; IL-1beta, interleukin 1beta; IL6, interleukin 6; IL-18, interleukin 18; IKK, IkB kinase; IRF3, interferon regulatory factor 3; MDA5, melanoma differentiation-associated protein 5; NF-kB, activation of nuclear factor kappaB; NLRP3, NLR family pyrin domain containing 3; RIG-I, retinoic acid-inducible gene I; ROS, reactive oxygen species; STING, stimulator of interferon gene; TBK1, TANK binding kinase 1; TLR9, toll-like receptor 9; TNFalpha, tumor necrosis factor alpha.
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IRAK, TRAF 6, etc. ( Figure 1 ). It has been proposed that the podocyte's role in innate immunity may predispose it to injury, depending on chronicity. Other family members include MDA5 and upon activation by recognition of viral RNA by cytoplasmic sensors, signal to the mitochondrial adaptor MAVS inducing an Interferon-regulatory factor (IRF)3, and IRF7-mediated type 1 IFN response ( Figure 1 ). TANK-binding kinase 1 (TBK1), which in turn activates nuclear interferon regulatory factor 3 (IRF3) and leads to the production of type I interferons ( Figure 1 ). The development of the cGAS-STING cytoplasmic defense system provides recognition of foreign nucleic acids, including pathogens/PAMPs, and DAMPs, as well as self-mitochondrial DNA leakage, cellular stress, and senescent break down products. This remarkably complex and efficient system based on the spatial coordination of DNA induced-cGAS-STING activity allows for antiviral immunity and balanced innate immune responses toward self-DNA.