Sepsis is a common and increasing cause of major morbidity and mortality in Australia, and worldwide. There is an urgent need for new adjunctive treatments. The dysregulated immune responses associated with sepsis have been a major target for clinical trials, yet, without success. Identification of new intervention strategies in septic patients likely requires consideration of host factors that are not traditionally associated with immune responses.
We observed differential expression of Wnt ligands, activators of a cell signalling network best known for its functions in embryonic development and tissue homeostasis, in blood of septic shock patients. Expression of a subset of Wnt ligands directly correlated with inflammatory markers, underpinning the emerging concept that Wnt signalling is integral to immune responses. Moreover, expression of other Wnts correlated with disease severity, encouraging assessment of Wnt expression in the quest for new biomarkers in septic patients.
Recent studies indicate that Wnt signalling regulates cytokine production and pathogen control. Pro-inflammatory as well as immune-regulatory functions have been suggested but mostly relied on in vitro observation. To define immune functions of Wnt ligands in vivo, we employ mouse models of acute bacterial infection and endotoxemia (LPS challenge). Differential expression of a subset of Wnt ligands was observed in spleen and liver upon LPS challenge and infection with Escherichia coli and Listeria monocytogenes. Inhibition of Wnt production reduced acute LPS-induced inflammatory responses. Furthermore, interference with Wnt signalling preserved host control of E. coli and enhanced control of Listeria in vivo and in vitro.
In summary, our findings suggest that the sum of Wnt signalling events in vivo promotes inflammatory cytokine production during bacterial infection. Furthermore, pharmacological intervention with the Wnt pathway offers opportunities to broadly dampen inflammatory cytokine production during acute bacterial infection while preserving host control of bacterial pathogens.