fig3

Figure 3. Inflammatory signaling pathways in DKD. The schematic summarizes the inflammatory signaling pathways that drive DKD. From left to right: NFκB pathway, JAK/STAT pathway, MAPK pathway, complement cascade, inflammasome signaling. NFκB remains inhibited and retained in the cytosol under physiological conditions. Activated pattern recognition receptors activate the IKK complex, which phosphorylates IκB, causing its degradation and freeing NFκB to translocate to the nucleus and activate target gene expression. Cytokine receptors dimerize upon detecting their cytokines, leading to transactivation of the associated JAKs. Activated JAK recruits and phosphorylates the transcription factor STAT, which then dimerizes and activates its target gene expression. MAPK pathway is a phosphorylation cascade resulting in activated MAPK translocating into the nucleus and transcribing target genes. When triggered, the complement system results in a cascade of proteolytic enzymes culminating in the formation of membrane attack complex and pro-inflammatory mediators. NFκB mediates the assembly of inflammasomes, which in turn release pro-inflammatory inducers and mediators. AGEs: Advanced glycation endproducts; DAMP: damage-associated molecular patterns; GSDMD: gasdermin D; IKK: IκB kinase; IL: interleukin; IκB: inhibitor of NFκB; JAK: Janus kinase; MAP2K: mitogen-activated protein kinase kinase; MAP3K: mitogen-activated protein kinase kinase kinase; MAPK: mitogen-activated protein kinase; MASP: MBL-associated serine protease; MBL: mannose-binding lectin; NFκB: nuclear factor kappa B; ROS: reactive oxygen species; STAT: signal transducer and activator of transcription; TF: transcriptional factor; Ub: ubiquitin.