Nucleic acids and endosomal pattern recognition: how to tell friend from foe? - PubMed (original) (raw)
Review
Nucleic acids and endosomal pattern recognition: how to tell friend from foe?
Eva Brencicova et al. Front Cell Infect Microbiol. 2013.
Abstract
The innate immune system has evolved endosomal and cytoplasmic receptors for the detection of viral nucleic acids as sensors for virus infection. Some of these pattern recognition receptors (PRR) detect features of viral nucleic acids that are not found in the host such as long stretches of double-stranded RNA (dsRNA) and uncapped single-stranded RNA (ssRNA) in case of Toll-like receptor (TLR) 3 and RIG-I, respectively. In contrast, TLR7/8 and TLR9 are unable to distinguish between viral and self-nucleic acids on the grounds of distinct molecular patterns. The ability of these endosomal TLR to act as PRR for viral nucleic acids seems to rely solely on the mode of access to the endolysosomal compartment in which recognition takes place. The current dogma states that self-nucleic acids do not enter the TLR-sensing compartment under normal physiological conditions. However, it is still poorly understood how dendritic cells (DC) evade activation by self-nucleic acids, in particular with regard to specific DC subsets, which are specialized in taking up material from dying cells for cross-presentation of cell-associated antigens. In this review we discuss the current understanding of how the immune system distinguishes between foreign and self-nucleic acids and point out some of the key aspects that still require further research and clarification.
Keywords: autoimmunity; endosomal toll-like receptors; innate immune activation; nucleic acids; pattern recognition.
Figures
Figure 1
Access of agonists to endosomal nucleic acid-sensing TLR. Endosomal TLR are situated in the membrane of the endolysosomal compartment of APC and sample the content of these compartments for the presence of nucleic acid agonists. Pathogens or dead cells gain access to the compartment by endocytosis. Alternatively, infection-induced autophagy can shuttle viral nucleic acids and antigens into the endolysosomal compartment and allow for recognition of replicating virus within infected cells by endosomal TLR.
Figure 2
Mechanisms for uptake of pathogens and dead cells. Material from pathogens and dead cells is taken up via the same uptake mechanisms, which include Fc receptor-, complement receptor- and scavenger receptor-mediated uptake. Fc receptor- and complement receptor-mediated uptake require the prior opsonisation of the cargo with antibodies and complement factors, respectively. APC activation is tightly regulated and influenced both by the source of the material and uptake route. Uptake of material from dying uninfected cells induces a number of regulatory pathways which attenuate pro-inflammatory immunogenic antigen-presenting cells (APC) activation. In contrast, uptake of pathogens or pathogen-derived material as associated with infected dying cells leads to pro-inflammatory immunogenic activation of APC.
Figure 3
How are nucleic acid-sensing TLR recruited to the endolysosomal compartment? (A) Nucleic acid sensing TLR traffic to the endolysosomal compartment from the endoplasmic reticulum (ER) via the Golgi apparatus. The chaperone protein UNC93B1 is necessary for successful migration of all three endosomal TLR, and adaptor protein (AP) complexes AP-2 an AP-4 are additionally required during the shuttle process of TLR9 and TLR7, respectively. TLR9, but not TLR7, is transiently located at the cell plasma membrane before reaching the endolysosome. Similarly, TLR3 has been detected at the cell surface in specific cell types. The reason for these differences in trafficking pathways for endosomal TLR is currently unknown. While in the ER and passing through the Golgi, TLR remain in an uncleaved state and only undergo cleavage to attain functional activation after arrival in the endolysosome. The requirement for cleavage is thought to be a protective mechanism to avoid unwanted TLR activation outside the endolysosomal compartment. (B) The induction and regulation of TLR recruitment to the endolysosomal compartment is still poorly understood. A small number of TLR have been detected in the endolysosomal compartment in the absence of activating stimuli suggesting the presence of a self-perpetuating low-frequency shuttling process of TLR to the endolysosome (steady-state recruitment). During infection, high frequency recruitment of TLR to the endolysosome takes place (induced recruitment). Induced recruitment is likely to be initiated by PAMP-activated TLR and/or other PRR. However, gatekeeper receptors controlling pathways such as the CD24-Siglec or CLR-Syk pathway have the ability to modulate and maybe even induce TLR recruitment to the endolysosomal compartment. The presence of gatekeeper receptors with the ability to distinguish specific signals from pathogens or uninfected host cells and to promote or regulate TLR recruitment is likely to play an important role in protecting the host from innate autoimmune activation.
Figure 4
The nuclear protein HMGB1 holds diverse functions in health and disease. HMGB1 is a ubiquitous nuclear DNA-binding protein. During apoptosis, the binding of HMGB1 to chromatin tightens, preventing the release of the cells' nucleic acids into surrounding tissue. In contrast, upon primary necrosis, complexes of HMGB1 and chromatin are released into the extracellular space. Such complexes act as alarmins, supporting tissue repair, and they have the capacity to stimulate cytoplasmic nucleic-sensing PRR and TLR. It is currently not entirely understood what factors favor the activation of a regulatory rather than an immunogenic response by HMGB1. HMGB1 is also released from antigen-presenting cells (APC) upon activation via PRR. After binding to nucleic acids in surrounding tissue, HMGB1 can act in an autocrine and paracrine fashion, signaling via a range of receptors including TLR2/4, RAGE, CXCR4, and CD24.
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