Toll-like receptor 7, Toll-like receptor 9, and Vacuolar-type H+-ATPase (TLR7/9 and V-ATPase)

The endosomal/lysosomal acidification machinery, primarily driven by the vacuolar-type H+-ATPase (V-ATPase), is essential for the functional activation of Toll-like receptors 7 and 9 (TLR7/9) (Forgac, 2007). TLR7 and TLR9 are endosomal receptors that recognize single-stranded RNA and unmethylated CpG DNA, respectively, triggering innate immune responses and the production of type I interferons (Kuznik et al., 2011). Acidification of the endosomal lumen is a prerequisite for the proteolytic cleavage of TLR7/9 by resident proteases like cathepsins, a step necessary for their signaling competence (Schrezenmeier & Dörner, 2020). Drugs such as hydroxychloroquine and chloroquine act as lysosomotropic weak bases that accumulate within endosomes, increasing the internal pH and thereby inhibiting the acidification machinery. This disruption prevents the activation of TLR7/9, making this pathway a critical therapeutic target in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (Wallace et al., 2012). Furthermore, this machinery is involved in viral entry and processing, providing a rationale for its investigation in infectious disease contexts.

Other names

TLR7TLR9V-ATPaseVacuolar-type H+-ATPaseEndosomal acidification machineryLysosomal acidification machinery

Inhibition of endosomal acidification (increasing pH), which prevents the proteolytic cleavage and activation of Toll-like receptor 7 and Toll-like receptor 9, thereby dampening the innate immune response (Schrezenmeier & Dörner, 2020).