Bacterial infections remain an important clinical problem despite our extensive arsenal of antibiotics. This is exemplified by lengthy treatments of chronic infections, high mortality due to impaired immune control and excessive inflammation, and an alarming increase in antibiotic resistance. New approaches to improve treatment options for challenging infections are needed. One attractive strategy is to enhance the host defence against pathogens without exacerbating infection-associated harmful inflammation.
We and others have previously associated the Wnt signalling pathway with tuberculosis, severe sepsis and Listeria infection and identified macrophages as a major source of Wnt proteins in patients. Wnt proteins are secreted signalling molecules well known as regulators of embryonic development and tissue homeostasis. Emerging concepts indicate that Wnt signalling regulates inflammatory cytokine production. Pro-inflammatory as well as immune-regulatory functions have been suggested but were mostly deduced from in vitro studies. Insights into immune functions of Wnt proteins in in vivo settings are needed.
Here we show differential expression of Wnt ligands in mouse models of TLR ligand-induced inflammation and acute infection with extracellular and intracellular bacterial pathogens. Interference with the Wnt pathway reduced TLR-induced inflammatory cytokine expression in vivo. During acute bacterial infection, interference with the Wnt pathway resulted in decreased bacterial burden in vivo and enhanced bacterial killing by macrophages. Furthermore, our data unexpectedly revealed that inhibition of Wnt/b-Catenin signalling impairs inflammatory cytokine responses in vivo, which is contrary to the recently proposed anti-inflammatory roles of b-Catenin activity downstream of Wnt signalling.
Taken together, our observations indicate that in vivo, Wnt pathway inhibition limits potentially harmful inflammation such as associated with immune-mediated lethality of severe infections, without compromising pathogen control. Thus, Wnt pathway inhibition meets highly desirable criteria, i.e. improved pathogen control while limiting inflammation, warranting its evaluation as a therapeutic target for severe infections.