ATP-degrading ENPP1 is required for survival (or persistence) of long-lived plasma cells

Hongsheng Wang,Zohreh Naghashfar,Javier Traba,Herbert C Morse,Jiafang Sun,Jeongheon Yoon,Sungyun Kang,Chenfeng Qi,Solomon Conteh,Yuanyuan Gao,Wendy Dubois,Patrick Duffy,Michael N Sack,Alexander L Kovalchuk,Shweta Jain,Sadia Abbasi,Dong-Mi Shin,Ines Gonzalez-Garcia

doi:10.1038/s41598-017-18028-z

Abstract

Survival of antibody-secreting plasma cells (PCs) is vital for sustained antibody production. However, it remains poorly understood how long-lived PCs (LLPCs) are generated and maintained. Here we report that ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is preferentially upregulated in bone marrow LLPCs compared with their splenic short-lived counterparts (SLPCs). We studied ENPP1-deficient mice (Enpp1−/−) to determine how the enzyme affects PC biology. Although Enpp1−/− mice generated normal levels of germinal center B cells and plasmablasts in periphery, they produced significantly reduced numbers of LLPCs following immunization with T-dependent antigens or infection with plasmodium C. chabaudi. Bone marrow chimeric mice showed B cell intrinsic effect of ENPP1 selectively on generation of bone marrow as well as splenic LLPCs. Moreover, Enpp1−/− PCs took up less glucose and had lower levels of glycolysis than those of wild-type controls. Thus, ENPP1 deficiency confers an energetic disadvantage to PCs for long-term survival and antibody production.

Highlights

Survival of antibody-secreting plasma cells (PCs) is vital for sustained antibody production
Staining of human bone marrow (BM) cells with a human-specific monoclonal anti-ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) antibody[40] revealed high expression of ENPP1 on PCs compared with naïve B cells (Fig. 1C). These results demonstrated that high expression of ENPP1 is associated with long-lived PCs (LLPCs) in BMs of both mice and humans
The development of durable protective antibody responses to vaccines or infections is critically dependent on the generation of LLPCs in the BM

Summary

Introduction

Survival of antibody-secreting plasma cells (PCs) is vital for sustained antibody production It remains poorly understood how long-lived PCs (LLPCs) are generated and maintained. The enzyme catalyzes 5′-phosphodiesterase bonds, mostly in ATP, to generate nucleoside 5′-monophosphates and inorganic pyrophosphate (PPi)[21,24], the latter being an inhibitor of mineral crystallization during the process of bone formation Consistent with this activity, mice with inactivating mutant alleles of Enpp[125,26] or a genetically engineered null allele[27] exhibit “stiff joints” and “tiptoe walking” due to excessive calcification of joints and paraspinal ligaments. ENPP1 is involved in adipocyte differentiation[35] and plays a role in carbohydrate metabolism and insulin resistance (reviewed in[36])

Methods

Results

Conclusion