IL-17 signaling pathway in monocytes drives the persistent inflammatory cytokine storm caused by Glaesserella parasuis infection in pigs.

Glaesserella parasuis, the causative agent of Glässer's disease, is a significant swine pathogen characterized by fibrinous polyserositis, meningitis, and arthritis, causing significant economic losses to the global swine industry. In this study, infection of piglets with G. parasuis induced a sustained systemic inflammatory response, marked by persistently elevated mRNA expression levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and acute-phase proteins (SAA, HP) in whole blood. This response was accompanied by severe inflammatory cell infiltration in the lungs, heart, spleen, and pericardium, contributing to high mortality rates. These findings suggest that G. parasuis triggers a persistent inflammatory cytokine storm in swine, however, the underlying molecular mechanisms had not been elucidated. Proteomic analysis of serum from piglets at 24, 48, and 72 h post-infection using time-course 4D-data-independent acquisition (4D-DIA) revealed that the IL-17 signaling pathway as a primary contributor. This finding was further supported by a progressive increase in the serum concentration of the IL-17A receptor (IL-17RA) throughout the infection period. Moreover, subsequent in vitro experiments demonstrated that expressions of IL-17A, IL-17RA, TRAF6, phosphorylated p65, JNK, and ERK were significantly upregulated in G. parasuis-infected monocytes. Collectively, this study establish that G. parasuis-infected monocytes activate NF-κB and MAPK signaling pathways by the IL-17RA/TRAF6 complex and suggest the IL-17 signaling pathway in monocytes as a driver of the persistent cytokine storm during G. parasuis infection.