Our results also suggest that blocking any portion of this axis will attenuate liver injury and neutrophil infiltration. However, our research cannot exclude the possibility that HMGB1 directly induces IL-17A production independent of IL-23. In addition to HMGB1, other DAMPs (such as DNA and cyclophilin A) have been reported to participate in activating the innate immune response.7, 21, 22 Except for TLR4, other receptors for HMGB1 may also stimulate the release of inflammatory http://www.selleckchem.com/products/Vorinostat-saha.html cytokines and should be further investigated. Macrophages can quickly respond

to endogenous stimulating factors after tissue injury.35 However, the role of macrophages in the acetaminophen-induced liver injury is controversial. Hepatic macrophages have been demonstrated to play a pathogenic role through their secretion of proinflammatory factors, such as tumor necrosis factor alpha (TNF-α), IL-1β, and NO.36 However, hepatic macrophages have also been reported to play a protective role through their secretion of regulatory factors, such as IL-10.37 This controversy stems from the effects of compounds used to inactivate (GdCl3) and deplete macrophages (clodronate/liposome).

Macrophages are heterogeneous and plastic, and at least two major macrophage populations exist, including classically activated macrophages (M1) and alternatively activated macrophages (M2).35 An induced macrophage (IM) population that differs from resident hepatic macrophages has been reported in acetaminophen-induced liver injury. IMs are formed from Anti-infection Compound Library circulating monocytes infiltrating the liver after acetaminophen treatment and exhibit phenotypes of alternatively activated macrophages. The absence of IMs delays the recovery of liver injury.38 However, resident hepatic macrophages isolated from normal livers have enhanced mRNA

expression of IL-1β and TNF-α after stimulation with DAMPs in vitro.24 Thus, selleck chemicals these studies demonstrate that hepatic resident macrophages are classically activated macrophages, which are prone to generating proinflammatory cytokines during acetaminophen-induced liver injury. In our study, macrophages also produced IL-23 after HMGB1 stimulation. γδ T cells were also able to produce IL-17A rapidly in response to DAMPs,18 and naïve γδ T cells produced IL-17 in response to IL-23 in the absence of TCR engagement,39 which was enhanced by the addition of IL-1β.40 In this study, IL-17 was dramatically elevated after acetaminophen treatment. Although NK and NKT cells are the dominant innate immune cells in murine liver,41 they did not produce IL-17A, which was confirmed by depleting NK and NKT cells with mAb (Fig. 3D). In our study, hepatic CD4+ T cells were not the major source of IL-17A, and CD4+ T cell depletion did not influence IL-17A production (Fig. 3C). Surprisingly, deletion of γδ T cells significantly reduced IL-17A production.