Deoxyguanosine is a TLR7 agonist

Area of Science:

• Immunology
• Innate Immunity
• Molecular Biology

Background:

• Toll-like receptor 7 (TLR7) is a key sensor of single-strand RNA (ssRNA) in the innate immune system.
• Structural studies reveal TLR7 possesses a secondary binding site for nucleosides, like guanosine, and can be activated by both nucleosides and ssRNA.
• Imidazoquinoline compounds, such as R848, also bind this nucleoside site and activate TLR7 independently of ssRNA.

Purpose of the Study:

• To investigate the potential of deoxyguanosine (dG) to activate TLR7 and induce immune responses.
• To determine the mechanism of dG-mediated TLR7 activation, including its dependence on RNA and endosomal maturation.

Main Methods:

• Treatment of murine bone marrow derived macrophages and plasmacytoid dendritic cells, and human peripheral blood mononuclear cells with dG.
• Measurement of cytokine production, including type I interferons, TNF, and IL-6.
• Assessment of TLR7 and MyD88 dependence, and the role of type I interferon receptor signaling and endosomal maturation.

Main Results:

• Deoxyguanosine (dG) triggered significant cytokine production in both murine and human immune cells.
• This dG-induced cytokine release was dependent on TLR7 and its adaptor MyD88, but not on type I interferon receptor signaling.
• Activation required endosomal maturation but did not necessitate the presence of RNA.

Conclusions:

• Deoxyguanosine (dG) acts as an agonist for Toll-like receptor 7 (TLR7).
• dG induces an inflammatory response through TLR7 in an RNA-independent manner.
• dG represents a novel class of RNA-independent TLR7 agonists.