| First Author | Zhang C | Year | 2018 |
| Journal | Cell Mol Immunol | Volume | 15 |
| Issue | 11 | Pages | 973-982 |
| PubMed ID | 28504245 | Mgi Jnum | J:347954 |
| Mgi Id | MGI:6756468 | Doi | 10.1038/cmi.2017.22 |
| Citation | Zhang C, et al. (2018) Macrophage-derived IL-1alpha promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell Mol Immunol 15(11):973-982 |
| abstractText | The metabolic intermediate of acetaminophen (APAP) can cause severe hepatocyte necrosis, which triggers aberrant immune activation of liver non-parenchymal cells (NPC). Overzealous hepatic inflammation determines the morbidity and mortality of APAP-induced liver injury (AILI). Interleukin-1 receptor (IL-1R) signaling has been shown to play a critical role in various inflammatory conditions, but its precise role and underlying mechanism in AILI remain debatable. Herein, we show that NLRP3 inflammasome activation of IL-1beta is dispensable to AILI, whereas IL-1alpha, the other ligand of IL-1R1, accounts for hepatic injury by a lethal dose of APAP. Furthermore, Kupffer cells function as a major source of activated IL-1alpha in the liver, which is activated by damaged hepatocytes through TLR4/MyD88 signaling. Finally, IL-1alpha is able to chemoattract and activate CD11b(+)Gr-1(+) myeloid cells, mostly neutrophils and inflammatory monocytes, to amplify deteriorated inflammation in the lesion. Therefore, this work identifies that MyD88-dependent activation of IL-1alpha in Kupffer cells plays a central role in the immunopathogenesis of AILI and implicates that IL-1alpha is a promising therapeutic target for AILI treatment. |
