Neutrophils exacerbate acetaminophen-induced liver injury by producing cytotoxic interferon-?

Background: Drug (e.g., acetaminophen, APAP)-associated hepatotoxicity is the major cause of acute liver failure. Emerging evidence shows that initial tissue damage caused by APAP triggers molecular and cellular immune responses, which can modulate the severity of hepatoxicity. The pro-inflammatory and cytotoxic cytokine interferon (IFN)-& gamma; has been reported as a key molecule contributing to APAP-induced liver injury (AILI). How-ever, its cellular source remains undetermined.Results: In the current study, we show that elevation of serum IFN-& gamma; in patients with drug hepatotoxicity cor -relates with disease severity. Neutralization of IFN-& gamma; in a mouse model of AILI effectively reduces hepatotoxicity. Strikingly, we reveal that IFN-& gamma; is expressed primarily by hepatic neutrophils, not by conventional immune cells with known IFN-& gamma;-producing capability, e.g., CD8+ T cells, CD4+ T cells, natural killer cells, or natural killer T cells. Upon encountering APAP-injured hepatocytes, neutrophils secrete cytotoxic IFN-& gamma; further causing cell stress and damage, which can be abrogated in the presence of blocking antibodies for IFN-& gamma; or IFN-& gamma; receptor. Furthermore, removal of neutrophils in vivo substantially decreases hepatic IFN-& gamma; levels concomitantly with reduced APAP hepatotoxicity, whereas adoptive transfer of IFN-& gamma;-producing neutrophils confers IFN-& gamma;-/-mice susceptibility to APAP administration.Conclusions: Our findings uncover a novel mechanism of neutrophil action in promoting AILI and provide new insights into immune modulation of the disease pathogenesis.

Automated summary

Drug-associated hepatotoxicity, particularly acetaminophen-induced liver injury (AILI), is a major cause of acute liver failure. This study reveals that serum levels of the pro-inflammatory cytokine interferon (IFN)- γ correlate with disease severity in patients with drug hepatotoxicity. The researchers found that hepatic neutrophils are the primary source of IFN- γ production in response to APAP-injured hepatocytes, and inhibition of IFN- γ effectively reduces hepatotoxicity.