Stromal Cell-Contact Dependent PI3K and APRIL Induced NF-κB Signaling Prevent Mitochondrial- and ER Stress Induced Death of Memory Plasma Cells

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

doi:10.1016/j.celrep.2020.107982

Rebecca Cornelis, Stefanie Hahne + Show 17 more

Open Access

https://doi.org/10.1016/j.celrep.2020.107982

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Abstract

SummaryThe persistence of long-lived memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, which are provided in niches organized by stromal cells. Using an ex vivo system in which we supply the known survival signals, direct cell contact to stromal cells, and the soluble cytokine a proliferation-inducing ligand (APRIL), we have elucidated the critical signaling pathways required for the survival of long-lived plasma cells. Integrin-mediated contact of bone marrow plasma cells with stromal cells activates the phosphatidylinositol 3-kinase (PI3K) signaling pathway, leading to critical inactivation of Forkhead-Box-Protein O1/3 (FoxO1/3) and preventing the activation of mitochondrial stress-associated effector caspases 3 and 7. Accordingly, inhibition of PI3K signaling in vivo ablates bone marrow plasma cells. APRIL signaling, by the nuclear factor κB (NF-κB) pathway, blocks activation of the endoplasmic-reticulum-stress-associated initiator caspase 12. Thus, stromal-cell-contact-induced PI3K and APRIL-induced NF-κB signaling provide the necessary and complementary signals to maintain bone marrow memory plasma cells.

Highlights

Plasma cells (PCs) can persist for long time periods in the bone marrow (BM)
PC survival was significantly improved when the cells were co-cultured with ST2 cells and in the presence of the cytokine a proliferation-inducing ligand (APRIL)
The transcription factor AP-1 (JunB, Jun, Fos) was highly expressed in PCs isolated from BM but was not or only marginally expressed in PCs cultivated for 3 days

Summary

Introduction

Plasma cells (PCs) can persist for long time periods in the bone marrow (BM). PCs are not intrinsically long lived (Makela and Nossal, 1962; Schooley, 1961) and die quickly when isolated and cultured in vitro, suggesting that their persistence in the BM depends on survival factors provided in the BM (Cassese et al, 2003). Antibodies against the adhesion molecules integrin aLb2 (lymphocyte-function-associated antigen [LFA-1]; CD11a/CD18) and integrin a4b1 (very late antigen [VLA-4]; CD49d/CD29), expressed by the PCs, ablate PCs from the BM (DiLillo et al, 2008) Ligands for both of these integrins, vascular cell adhesion molecule 1 (VCAM; CD106) and intercellular adhesion molecule 1 (ICAM; CD54), are expressed by BM stromal cells, suggesting that integrin-mediated binding of PCs to stromal cells might directly, by the focal adhesion kinase/phosphatidylinositol 3-kinase (PI3K) pathway (Giancotti and Ruoslahti 1999; Parsons et al, 2000) promote PC persistence in the BM. Whether or not BCMA signaling and contact to stromal cells are sufficient to maintain the survival of memory PCs and how they prevent death of the PC have not been elucidated

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