Fig. 1

Different signaling pathways are involved in the inflammatory regulation of IFN-I. A After being stimulated by bacteria, viruses, PAMP/DAMP, etc. in the external environment, the DNA sensors activate STING, which moves to the Golgi and is phosphorylated by TBK1, allowing for the phosphorylation and activation of IRF 3. Upon binding to their ligands, RIG-I and MDA5 engage MAVS, leading to activation of TBK1 and members of the IKK family of kinases. Similarly, TLRs signal through MyD88 and TRIF adaptor molecules, leading to the activation of TBK1 and members of the IKK family. These kinases trigger the phosphorylation, activation, and dimerization of IRFs and the release of NF-κB. IRFs and NF-κB then migrate into the nucleus where they bind to promoter regions of IFN-I and other target genes, thereby stimulating IFN-I as well as anti-inflammatory and pro-inflammatory cytokine gene transcription. B In the canonical IFN-I signaling pathway, IFN-I binding with IFNAR results in the phosphorylation of JAK1 and TYK2, which then recruit and activate STAT proteins, leading to their trimerization or dimerization and nuclear translocation. Two distinct transcriptional complexes are formed, which regulate the expression of different ISGs' in a sequence-dependent manner. ISGF3, a trimerized complex formed by STAT1, STAT2, and IRF 9, recognizes the ISRE motif and induces a group of gene expression. The other complex formed by STAT1 homodimers binds to the GAS motif and mainly active inflammatory gene expression. B In the uncanonical IFN-I signaling pathway, IFN-I can also induce a set of genes expression independent of STATs, such as MAPKs and PI3K pathways. Additionally, IFN regulates some ISGs’ translation through the mTOR signaling pathway