Double-stranded RNA and Toll-like receptor activation: a novel mechanism for blood pressure regulation

Abstract

Toll-like receptors (TLRs), such as TLR4 and 9, recognize pathogen-associated molecular pattern (PAMPs) and danger-associated molecular patterns (DAMPs) and are associated with increased blood pressure (BP). TLR3, residing in the endosomal compartment, is activated by viral double-stranded RNA (dsRNA) leading to activation of TIR receptor domain-containing adaptor inducing IFN-β (TRIF) dependent pathway. Besides foreign pathogens, the immune system responds to endogenous markers of cellular damage such as mitochondrial dsRNA (mtdsRNA). New evidence has shown a link between dsRNA and increased BP. Moreover, TLR3 activation during pregnancy was demonstrated to develop preeclampsia-like symptoms in both rats and mice. Hence, we hypothesize that the dsRNA derived from viral nucleic acids or cellular damage (mtdsRNA) will increase the inflammatory state through activation of TLR3, contributing to vascular dysfunction and increased BP. Therefore, inhibition of TLR3 could be a therapeutic target for the treatment of hypertension with potential improvement in vascular reactivity and consequently, a decrease in BP.

Keywords: TLR3; hypertension; mitochondrial dsRNA.

Figure 1.. dsRNA–TLR3 signaling cascade

dsRNA is internalized by cell surface receptors via endocytosis and then recognized by TLR3 present in the endosome leading to subsequent signaling via the adaptor protein TRIF. Further, dsRNA can also be recognized by cytoplasmic RNA helicase RIG-I (retinoic acid-inducible gene I) and melanoma differentiation-associated gene-5 (MDA5) into the cytoplasm through SID transporter. Abbreviations: dsRNA, double-stranded RNA; TLR3, toll-like receptor 3; RIG-I, a retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated gene. Adapted from Nguyen et al. [45] (permission obtained under license number 4757830360815).

Figure 2.. The schematic hypothesis of the proposed mechanisms of TLR3-inhibition to prevent hypertension

dsRNA derived from viral nucleic acids or cellular damage trigs TLR3 leading to the production of inflammatory cytokines and IFN, contributing to vascular dysfunction and increased blood pressure. Inhibition of TLR3 could potentially improve vascular reactivity and consequently, decreases blood pressure. Abbreviations: dsRNA, double-stranded RNA; IFN, interferon; mtdsRNA, mitochondrial dsRNA; TLR3, toll-like receptor 3. Key references: [13,61,91].