Innate-like function of memory Th17 cells for enhancing endotoxin-induced acute lung inflammation through IL-22.

Abstract

Lipopolysaccharide (LPS)-induced acute lung injury (ALI) is known as a mouse model of acute respiratory distress syndrome; however, the function of T-cell-derived cytokines in ALI has not yet been established. We found that LPS challenge in one lung resulted in a rapid induction of innate-type pro-inflammatory cytokines such as IL-6 and TNF-α, followed by the expression of T-cell-type cytokines, including IL-17, IL-22 and IFN-γ. We discovered that IL-23 is important for ALI, since blockage of IL-23 by gene disruption or anti-IL-12/23p40 antibody treatment reduced neutrophil infiltration and inflammatory cytokine secretion into the bronchoalveolar lavage fluid (BALF). IL-23 was mostly produced from F4/80(+)CD11c(+) alveolar macrophages, and IL-23 expression was markedly reduced by the pre-treatment of mice with antibiotics, suggesting that the development of IL-23-producing macrophages required commensal bacteria. Unexpectedly, among T-cell-derived cytokines, IL-22 rather than IL-17 or IFN-γ played a major role in LPS-induced ALI. IL-22 protein levels were higher than IL-17 in the BALF after LPS instillation, and the major source of IL-22 was memory Th17 cells. Lung memory CD4(+) T cells had a potential to produce IL-22 at higher levels than IL-17 in response to IL-1β plus IL-23 without TCR stimulation. Our study revealed an innate-like function of the lung memory Th17 cells that produce IL-22 in response to IL-23 and are involved in exaggeration of ALI.