Figure 1

Pathways leading to the type I interferon production. Among the family of Toll-like receptors (TLRs), TLR3, TLR4, TLR7/8 and TLR9 are known to induce production of type I interferons in various cells. Surface TLR4 recognizes lipopolysaccharides (LPS) from bacterial cell walls and trasmit the signal downstream via MyD88-dependent or MyD88-independent pathways resulting in phosphorylation, dimerization and nuclear translocation of IRF5 and IRF3, and activation of NF-κB and mitogen-activated protein kinase (MAPK) pathways. Intracellular TLR3, TLR7/8 and TLR9 residing in the endosomes are activated by viral double-stranded (ds)RNA, single-stranded RNA and unmethylated dsDNA, respectively. TLR3 signals via adaptor TRIF and activates IRF3, NF-κB and MAPK pathways. TLR7/8 and TLR9 transmit the signal via the adaptor molecule MyD88. The intracellular form of osteopontin 1 (SPP1) binds to MyD88 upon ligation of TLR9 with unmethylated CpG oligonucleotides and promotes induction of IFNα genes in mouse plasmacytoid dendritic cells (pDCs). TLR7 and TLR9 are the only receptors expressed in pDCs, while other cells contain other TLRs as well. Detection of nucleic acids by TLRs in intracellular endosomes prevents immune responses to the host self-DNA. Normally, nucleic acids released by dying necrotic or apoptotic cells undergoing rapid degradation by nucleases, DNaseI and DNaseIII (TREX1), while bacterial or viral nucleic acids are protected by the cell wall or viral capsid and could be detected by TLRs only after penetrating the cell. Breach of tolerance to self-DNA and activation of pDCs could happen if self-DNA remains undegraded due to defective function of the nucleases and meet endosomal TLR9. Cationic antimicrobial peptide LL37 and high-mobility group box 1 protein (HMGB1) released by damaged or infected cells, mainly keratinocytes and neutrophils, bind DNA making it resistant to degradation and facilitate endocytosis of DNA through the lipid rafts and receptor for advanced glycation end-products (RAGE), delivering it to TLR9. DNA/DNA-protein aggregates could be recognized by anti-DNA/anti-RNA-binding proteins (anti-RNP) antibodies produced by the autoreactive B cells. Binding of these immune complexes to the low-affinity Fcγ receptors II leads to their internalization and translocation to the endosomes containing TLR9. Viral DNAs residing in the cytoplasm could be detected by two cytoplasmic DNA sensors, DNA-dependent activator of interferon regulatory factors (DAI) and absent in melanoma 2 (AIM2), which trigger induction of type I interferon genes through TBK1-mediated and IRF3-mediated signalling. AIM2 also activates caspases 1 and 3 by recruiting adaptor ASC (apoptosis-associated speck-like protein containing a CARD) and forming an inflammasome that promotes release of IL-1β and IL-18. Two RNA helicases, retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated gene 5 (MDA-5), detect viral RNAs in the cytoplasm. Activated RIG-1 and MDA-5 interact with adaptor protein MAVS anchored by its C-terminal domain to a mitochondrion. This interaction triggers signalling through TRAF3 and TRAF6 adaptors and results in activation of IRF3, IRF7 and NF-κB pathway. Autophagosomes can engulf the replicating viral RNAs and, after fusion with endosomes, present it to the TLR7/8. Viral RNAs can induce a common antiviral defence mechanism aimed at blocking viral replication through total inhibition of cellular transcription and translation. Thus, dsRNAs activate 2',5'-oligoadenylate synthase (OAS) producing 2',5'-oligoadenylates, which in turn activate the latent nuclease RNase L, resulting in the degradation of all cytoplasmic RNAs. Another pathway targets protein synthesis machinery by protein kinase dsRNA-dependent serine-threonine kinase (PKR), which inactivates the alpha subunit of initiation factor eIF2, resulting in rapid inhibition of protein translation. The latter two pathways may induce apoptosis of the infected cell. Yellow stars, genes with strong evidence for association with autoimmune diseases; black stars, genes with inconsistent association. ISG, interferon stimulated genes; PI3K, phosphoinositide 3-kinase.