Defining the role of neutrophils in paracetamol-induced liver injury and regeneration

Abstract

Neutrophils, the most abundant white blood cell in mammals, are crucial innate immune cells required as the first line of defence against invading pathogens or foreign material. They are also recruited in response to sterile tissue injury and play significant roles in coordinating both the innate and adaptive immune reactions. Their response and actions during acetaminophen (APAP) induced acute liver injury (ALI) is controversial. APAP-ALI is the leading cause of liver injury-induced death in the western world and treatments remain limited with >50% of patients not surviving after progressing to hepatic failure. Most publications indicate neutrophils contribute to APAP-ALI progression, but recent reports have highlighted their reparative function in this condition, through communications with monocyte derived macrophages (MDM)s. Studies in other organs and models of disease have also recently shown beneficial neutrophil functions, but the controversy persists in APAP-ALI. Specifically, the neutrophil reparative mechanisms require further investigation to enable exploitation to improve the outcome of patients suffering APAP-ALI. Here we show that neutrophils contribute both to hepatic damage and to tissue repair during APAP-ALI. We show that this dichotomy of function is time dependent through a combination of selective cyclin-dependent kinase inhibitor (CDKI) mediated neutrophil depletion in WT mice and through genetic KO of formylated peptide receptor 1 (FPR1) mediated neutrophil activation. Preventing FPR1 mediated hepatic neutrophil migration and activation, including myeloperoxidase activity resulted in reduced inflammation and hepatic damage. This genetic manipulation also reduced hepatic repair with no improvement of necrosis from 24 to 48 h post injury. Without FPR1 mediated neutrophil activation there was reduced hepatic extracellular matrix remodelling and angiogenesis. Early CDKI mediated neutrophil depletion reduced hepatic injury and late depletion resulted in a proinflammatory monocyte macrophage phenotype, reduced hepatic repair and hepatocyte proliferation. Identifying this time dependent divergent function of neutrophils in APAP-ALI resolves some of the literature controversy and highlights the importance of neutrophils in recovery from APAP-ALI. Although reducing neutrophil number and activity can reduce injury, the overall and final effect may be detrimental to tissue repair and therefore patient recovery.