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. 2014 Jul 25;5:279. doi: 10.3389/fphys.2014.00279

Figure 2.

Figure 2

Proinflammatory properties of plasmacytoid dendritic cells (pDCs). pDCs are capable to sense a variety of pathogen-associated molecular patterns (PAMPs) such as viral and bacterial peptides, peptidoglycans, lipopolysaccharides (LPS), RNA, and DNA through a range of pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), double strand RNA-sensing receptor helicases (PRK, RIG-1, MDA5, and LGP2), and cytoplasmic receptors recognizing viral RNA and DNA (LRRFIPI, cGAS, DAI, DDX, and DNA polymerase III) or peptides (NOD1 and NOD2). TLR3, TLR7, TLR8, and TLR9 recognize pathogen-associated molecules in intracellular exosomes. PAMP-induced activation of PRRs leads to the activation of interferon-regulating factors IRF-3 and IRF-7 and transcription factor NF-κB that drive transcription of Type I interferon (IFN) genes such as IFN-α and IFN-β. In response to infection, pDCs secrete large amounts of IFN-α and IFN-β that display a variety of stimulatory activities on innate and adaptive immunity through activation of phagocytic and cytotoxic activities of macrophages, antigen-presenting function of conventional DCs (cDCs) and production of proinflammatory cytokines (interleukin(IL)-12, tumor necrosis factor (TNF)-α, and IFN-γ. IFN-I-induced up-regulation of IFN-γ production by natural killer (NK) cells and T cells is of great value since IFN-γ is a potent antiviral agent. IFN-I also inhibit virus replication and invasion and arrest bacterial proliferation. IFN-I is able to induce a positive feedback autocrine response through binding to the IFN-α/β receptor (IFNAR) on the surface of pDCs. The activation of the IFNAR leads to the recruitment of IRF9 that forms a heterotrimeric transcription complex IGGF3 (IFN-stimulated gene factor) capable to recognize specific regulatory motifs called interferon-stimulated response elements (ISRE) in the promoter regions of IFN-I-inducible target genes. As a result, many genes are expressed including PRRS, chemokines, caspases, inflammasome (cryopyrin, Nlrp3), and apoptotic cell surface death receptor Fas. Caspase-1 and caspase-11 are required for the activation of inflammasome components and IL-1β. Release of IL-1β and inflammasome induce death of infected cells through the pypoptotic mechanism and activates inflammatory response. pDCs also secrete IL-6 and TNF-α that activate cDCs and stimulate B cell differentiation to antibody-producing cells. pDCs could display cytotoxic properties in an IL-3-dependent manner. IL-3 produced by activated T cells could activate signaling pathway mediated by signal transducers and activator of transcription (STAT)3 and STAT5 and induce expression of granzyme B (GZMB), whose release causes death of infected host cells.