Background The involvement of mitochondrial oxidative phosphorylation (OXPHOS) in mast cell exocytosis was recently suggested by the finding that mitochondria translocate to exocytosis sites upon mast cell activation. In parallel, mitochondrial signal transducer and activator of transcription 3 (STAT3) was found to be involved in ATP production. However, the regulation of mitochondrial STAT3 function and its connection to mast cell exocytosis is unknown. Objective We sought to explore the role played by mitochondrial STAT3 in mast cell exocytosis. Methods Experiments were performed in vitro with human and mouse mast cells and rat basophilic leukemia (RBL) cells and in vivo in mice. OXPHOS activity was measured after immunologic activation. The expression of STAT3, extracellular signal-regulated kinase 1/2, and protein inhibitor of activated STAT3 in the mitochondria during mast cell activation was determined, as was the effect of STAT3 inhibition on OXPHOS activity and mast cell function. Results Here we show that mitochondrial STAT3 is essential for immunologically mediated degranulation of human and mouse mast cells and RBL cells. Additionally, in IgE-antigen-activated RBL cells, mitochondrial STAT3 was phosphorylated on serine 727 in an extracellular signal-regulated kinase 1/2-dependent manner, which was followed by induction of OXPHOS activity. Furthermore, the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3, was found to inhibit OXPHOS activity in the mitochondria, resulting in inhibition of mast cell degranulation. Moreover, mice injected with Stattic, a STAT3 inhibitor, had a significant decrease in histamine secretion. Conclusion These results provide the first evidence of a regulatory role for mitochondrial STAT3 in mast cell functions, and therefore mitochondrial STAT3 could serve as a new target for the manipulation of allergic diseases.
Bibliographical noteFunding Information:
Supported by the United States Binational Science Foundation (to E.R.), the Israeli Academy of Science (to E.R.), The German-Israel Foundation for Scientific Research and Development (to E.R.), the National Research Foundation of Singapore (HUJ-CREATE; to E.R.), and the Morasha Foundation Fund (to H.N.). Z.Y. was supported by the Canadian Friends of Hebrew University .
Disclosure of potential conflict of interest: T. H. Erlich, Z. Yagil, G. Kay, A. Peretz, H. Migalovich-Sheikhet, S. Tshori, and E. Razin have received research support from the Israeli Academy of Science , BSF , NRF , and GIF . H. Nechushtan has received research support from the Morasha Foundation Fund . F. Levi-Schaffer has received research support from the Israeli Ministry of Industrial Trade and is a board member for the Israeli Ministry of Health. A. Saada declares that she has no relevant conflicts of interest.
- mast cells