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Stromal cell-contact dependent PI3K and APRIL induced NF-κB signaling complement each other to prevent mitochondrial- and endoplasmic reticulum stress induced cell death of bone marrow plasma cells

By Rebecca Cornelis, Stefanie Hahne, Adriano Taddeo, Georg Petkau, Darya Malko, Pawel Durek, Manja Thiem, Lukas Heiberger, Elodie Mohr, Cora Klaeden, Koji Tokoyoda, Francesco Siracusa, Bimba Franziska Hoyer, Falk Hiepe, Mir-Farzin Mashreghi, Fritz Melchers, Hyun-Dong Chang, Andreas Radbruch

Posted 21 Nov 2019
bioRxiv DOI: 10.1101/849638

Persistence of long-lived, memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, provided in niches organized by stromal cells. Here we describe that ex vivo we can prevent apoptosis of bone marrow plasma cells by supplying direct cell contact with stromal cells and the soluble cytokine APRIL. Integrin-mediated contact of bone marrow plasma cells with stromal cells activates the PI3K signaling pathway, leading to critical inactivation of FoxO1/3 and preventing the activation of mitochondrial stress-associated effector caspases 3 and 7. Likely, inhibition of PI3K signaling in vivo ablates bone marrow plasma cells. APRIL signaling, via the NF-kB pathway, blocks activation of the endoplasmic reticulum stress-associated initiator caspase 12. Thus, stromal cell-contact induced PI3K and APRIL-induced NF-kB signaling provide necessary and complementary signals to maintain bone marrow memory plasma cells.

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