Neutrophils regulate ITPR2 levels in epithelia by direct injection of elastase

Abstract

The destructive role of neutrophils in inflammation is well known1 but they also have less damaging effects such as tissue remodeling and modulation of metabolism2, 3. Usually, neutrophils in tissues release toxic or digestive compounds into the extracellular region4-8. Here we report that neutrophils can inject their granule contents directly into hepatocytes. Neutrophil elastase within the hepatocytes selectively degrades the inositol trisphosphate receptor (ITPR), especially the type 2 isoform which is the predominant intracellular calcium release channel in these cells9. This action reduces calcium signals and cell proliferation without cellular damage. In response, the hepatocytes increase expression of serpins E2 and A3, which block the effect of elastase. This phenomenon is also observed in liver biopsies from patients with alcoholic hepatitis, a condition characterized by infiltration of neutrophils10, 11. This non-destructive and reversible effect on hepatocytes defines a previously unappreciated role of neutrophils in transiently regulating signaling mechanisms in epithelia.