Elevated Expression of IL-23/IL-17 Pathway–Related Mediators Correlates With Exacerbation of Pulmonary Inflammation During Polymicrobial Sepsis

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Abstract
Sepsis is a leading cause of death in the United States, claiming more than 215,000 lives every year. A primary condition observed in septic patients is the incidence of acute respiratory distress syndrome, which is characterized by the infiltration of neutrophils into the lung. Prior studies have shown differences in pulmonary neutrophil accumulation in C57BL/6J (B6) and A/J mice after endotoxic and septic shock. However, the mechanism by which neutrophils accumulate in the lung after polymicrobial sepsis induced by cecal ligation and puncture still remains to be fully elucidated. We show in this study that lung inflammation, characterized by neutrophil infiltration and expression of inflammatory cytokines, was aggravated in B6 as compared with A/J mice and correlated with a high expression of p19, the interleukin 23 (IL-23)–specific subunit. Furthermore, lipopolysaccharide stimulation of B6- and A/J-derived macrophages, one of the main producers of IL-23 and IL-12, revealed that B6 mice favored the production of IL-23, whereas A/J-derived macrophages expressed higher levels of IL-12. In addition, expression of IL-17, known to be upregulated by IL-23, was also more elevated in the lung of B6 mice when compared with that in the lung of A/J mice. In contrast, pulmonary expression of interferon-γ was much more pronounced in A/J than that in B6 mice, which was most likely a result of a higher production of IL-12. The expression of the IL-17–dependent neutrophil recruitment factors chemokine (CXC motif) ligand 2 and granulocyte colony-stimulating factor was also higher in B6 mice. Altogether, these results suggest that increased activation of the IL-23/IL-17 pathway has detrimental effects on sepsis-induced lung inflammation, whereas activation of the IL-12/interferon-γ pathway may lead, in contrast, to less pronounced inflammatory events. These two pathways may become possible therapeutic targets for the treatment of sepsis-induced acute respiratory distress syndrome.

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