Eosinophils secrete IL-4 to facilitate liver regeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-06, Vol.110 (24), p.9914-9919
• Main Authors: Goh, Y. P. Sharon, Henderson, Neil C., Heredia, Jose E., Eagle, Alex Red, Odegaard, Justin I., Lehwald, Nadja, Nguyen, Khoa D., Sheppard, Dean, Mukundan, Lata, Locksley, Richard M., Chawla, Ajay
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; blood proteins; Cell cycle; Cell Cycle - genetics; Cell Cycle - physiology; Cell Proliferation; compensatory growth; Cytokines; DNA replication; Eosinophils; Eosinophils - secretion; Gene Expression Profiling; Genotypes; Hepatectomy; Hepatocytes; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - physiology; hormones; Immunoblotting; interleukin-4; Interleukin-4 - genetics; Interleukin-4 - metabolism; Interleukin-4 Receptor alpha Subunit - genetics; Interleukin-4 Receptor alpha Subunit - metabolism; Liver; Liver - metabolism; Liver - physiology; Liver - surgery; Liver diseases; Liver regeneration; Liver Regeneration - genetics; Liver Regeneration - physiology; Macrophages; Male; Metabolites; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; nutrients; Oligonucleotide Array Sequence Analysis; Physical trauma; regrowth; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Signal Transduction - physiology; Tissue repair; Toxins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1304046110

The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin-or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4 Rot in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.