Premium
Cross‐talk Among Kupffer Cells and Hepatic Stellate Cells is Critical for Kupffer Cell Activation during Liver Injury
Author(s) -
Roth Katherine,
Copple Bryan,
Albee Ryan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.56.2
Subject(s) - kupffer cell , hepatic stellate cell , liver cytology , microbiology and biotechnology , liver injury , tumor necrosis factor alpha , biology , inflammation , macrophage , cytokine , immunology , endocrinology , in vitro , biochemistry , liver metabolism
The mechanisms that regulate Kupffer cell activation in the liver after injury are not fully understood. Our recent studies demonstrated that activation of hypoxia‐inducible factor‐1a (HIF‐1α) in hepatic stellate cells (HSCs) is critical for Kupffer cell activation after liver injury. This indicates that cross‐talk among HSCs and Kupffer cells during liver injury is critically important for Kupffer cell activation. In our current studies, we tested the hypothesis that necrotic hepatocytes activate HIF‐1a in HSCs which stimulates release of a mediator that activates Kupffer cells. Our results demonstrate that treatment of primary, mouse HSCs with necrotic hepatocytes activates HIF‐1a. Necrotic hepatocytes failed to activate HIF‐1a in HSCs isolated from MyD88 knockout mice or in HSCs pretreated with the NF‐kB inhibitor MG132. This indicated a key role for toll‐like receptor and/or interleukin receptor signaling in activation of HIF‐1a in HSCs by necrotic hepatocytes. Treatment of Kupffer cells with necrotic hepatocytes did not increase expression of inflammatory cytokines, however, treatment of Kupffer cells with conditioned medium from HSCs treated with necrotic hepatocytes upregulated Cxcl2 and other inflammatory cytokines in Kupffer cells. Pretreatment of HSCs with the phospholipase A2 inhibitor, methyl arachidonyl fluorophosphonate, prevented HSC‐mediated Kupffer cell activation, suggesting that HSCs release an arachidonic acid metabolite after exposure to necrotic hepatocytes that activates Kupffer cells. In conclusion, these in vitro studies support our in vivo findings, and expand upon these studies by demonstrating that necrotic cells activate HIF‐1α in HSCs in a Myd88‐ and NF‐kB‐dependent manner, leading to the release of an arachidonic acid metabolite that activates Kupffer cells. Further characterization of this pathway could lead to the development of therapies aimed at reducing Kupffer cell‐mediated liver injury or increasing Kupffer cell‐mediated liver repair. Support or Funding Information This study was supported by NIH grant 2 R01 DK073566 to Bryan Copple. Katherine Roth was supported by NIH Training Grant T32 ES007255.