ダサチニブは微粒子によるパイロトーシスと急性肺炎を抑制する

抄録

Irritating particulates like PM2.5 cause inflammatory diseases. Such particulates cause phagolysosomal dysfunction of immune cells, resulting in the activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, an immune complex that induces cell death accompanied by the release of inflammatory mediators, namely pyroptosis. However, targeting NLRP3 inflammasome-associated responses is insufficient in treating relevant inflammatory diseases, as several particulates like silica particle (SP) also induce NLRP3-independent cell death and release of the inflammatory mediators like interleukin-1(IL-1) α. Therefore, drugs suppressing particulate-induced NLRP3-independent pyroptosis are warranted. In this study, we screened the compounds that can inhibit SP-induced cell death and IL-1α release using a high-content imaging-based system. As a result, we found that several Src family kinase (SFK) inhibitors, including dasatinib, effectively suppressed particulate-induced cell death and IL-1α release. Dasatinib reduced SP-induced phagolysosomal dysfunction. Moreover, dasatinib treatment suppressed the increase in IL-1α levels, and neutrophil count in SP-induced NLRP3-independent acute lung inflammation. In conclusion, dasatinib can inhibit particulate-induced pyroptosis by suppressing the phagolysosomal dysfunction and can be used to treat the relevant disease.