The first line of defense that protects the host against pathogens is the innate immune system that initiates inflammation against pathogen invasion. This is achieved by producing inflammatory cytokines and chemokines that activate inflammatory cells.
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Excessive stimulation of cytokines and chemokines can cause harmful chronic inflammation or autoimmune diseases; therefore, this process is strictly regulated. Innate immune cells are equipped with pathogen sensors called pathogen recognition receptors (PRRs). These PRRs can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) of endogenous molecules that may be caused by tissue injury. These PRRs can sense nucleic acids and are called nucleic acid sensors, and there are two types: DNA and RNA sensors. In this article, we will focus on RNA sensors.
Types of RNA Sensors
There are two main types of RNA sensors: toll-like receptors (TLRs) and the retinoic-acid inducible gene-I (RIG-I)-like receptors (RLRs).
TLRs are localized on cell surfaces and endosomal compartments of cells such as dendritic cells and macrophages. TLR3 is an example of an RNA sensor, and it identifies double-strand RNA of various viral genomes and the replication genomes. Extracellular RNA has to go under endocytosis to access the TLRs, and this is done by selective RNA uptake into endosomes/lysosomes.
RLRs are cytosolic sensors and include three members: RIG-I, melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). RIG-I identifies RNA in the cytoplasm of infected cells and initiates an immune response. MDA5 identifies longer dsRNA, and LGP2 enables the interactions between MDA5 and dsRNA. This binding then initiates conformation modification of RIG-I and MDA5 that induce interferon release and immune activation. Although RNA sensors are important for the rapid detection of non-self RNA, there is also a potential risk of self-RNA recognition that might induce autoimmune diseases.
Other emerging RNA sensors have been identified, such as NOD-like receptors (NLRs) and DEAD-box or DEAH-box RNA helicases. These RNA sensors are believed to sense RNA and interact with TLRs and RLRs to trigger an immune response.
RNA sensors in viral diseases
Viruses utilize the host's cell machinery to replicate and infect the host. The viral RNA contains PAMPs, enabling PRR to identify these molecules and alert the immune system to trigger an immune response. These RNA sensing can be detected by endosomal and cytosolic PRR and then promotes various signaling cascades that trigger the production of numerous pro-inflammatory molecules and enhance the expression of genes that will further aid in attacking the viral infection.
Viruses also have many strategies to evade TLE and RLR identification, which have been researched. These strategies include masking or modifying RNA and antagonizing RNA sensors via direct binding or inhibiting the downstream signaling mechanisms.
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RNA sensors in cancer
TLRs are also expressed on malignant epithelial cells and can cause apoptosis in several kinds of tumors. The expression of TLR RNA sensors and the intracellular signaling pathway can differ, which can influence the tumor microenvironment (TME). Cancer cells sense and respond to RNA by secreting cytokines and chemokines that increase immune cell activation.
TLR3 is a potential target to enhance anti-tumor activity, as studies have shown that its expression is increased in tumor tissues. In lung cancer, TLR3 expression is associated with stimulated CD103+ lung dendritic cells and inducing apoptosis.
RLRs can sense RNA in the cytoplasm and are expressed in several normal and cancer cells. RIG-I signaling stimulates immune activation in TME and promotes transcriptional activation of pro-inflammatory genes and cytokines. RIG-I signaling triggers apoptosis in melanomas via inducing surface expression of membrane-bound TRAIL (TNF-related apoptosis-inducing ligand) in natural killer cells and a cytotoxic NK response.
RNA sensor agonists are also used in cancer immunotherapy. TLR agonists have been well-researched in their role as targets for cancer immunotherapy. This is due to their ability to initiate the expression of immune cells and inflammation in an immunosuppressive TME. This strong recruitment of immune cells, such as T-cells, can directly target tumor cells.
The role of RNA sensors in cancer research and therapy is vast and utilizes various other mechanisms, such as immune checkpoint therapy and cancer vaccines.
RNA sensors are critical for protecting the host from exogenous and endogenous RNA from diverse infections to tissue injuries. PRR can be expressed in different cell types and locations, allowing for vast diversity. This diversity enables the host to tailor the response to different pathogens with different strategies. RNA sensors also have various clinical applications and have great potential in cancer therapy. They also play important roles in cellular RNA metabolism and antiviral functions, which can contribute to antiviral immunity. However, further advancement in these areas requires a deep understanding of the mechanism that activates and regulates RNA sensors.
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