miR‐148a controls metabolic programming and survival of mature CD19‐negative plasma cells in mice

Abstract

Long-lived antibody-secreting plasma cells are essential to establish humoral memory against pathogens. While a regulatory transcription factor network has been established in plasma cell differentiation, the regulatory role of miRNAs remains enigmatic. We have recently identified miR-148a as the most abundant miRNA in primary mouse and human plasma cells. To determine whether this plasma cell signature miRNA controls the in vivo development of B cells into long-lived plasma cells, we established mice with genomic, conditional, and inducible deletions of miR-148a. The analysis of miR-148adeficient mice revealed reduced serum Ig, decreased numbers of newly formed plasmablasts and reduced CD19-negative, CD93-positive long-lived plasma cells. Transcriptome and metabolic analysis revealed an impaired glucose uptake, a reduced oxidative phosphorylation-based energy metabolism, and an altered abundance of homing receptors CXCR3 (increase) and CXCR4 (reduction) in miR-148a-deficient plasma cells. These findings support the role of miR-148a as a positive regulator of the maintenance of longlived plasma cells.

FOXM1 regulates glycolysis and energy production in multiple myeloma

“…Our results on FOXM1-dependent activation of myeloma metabolism agree with evidence that metabolic reprogramming, a hallmark of human cancer, is important for MM [ 25 ]. Compared to normal long-lived plasma cells, which exhibit a high rate of glucose consumption [ 26 ] due to a high physiological demand for antibody glycosylation [ 27 ], neoplastic plasma cells feature further increases in metabolic activity [ 28 ] together with characteristics of metabolic remodeling that are typical of the Warburg effect: aerobic glycolysis, elevated glucose consumption, and increased lactate production [ 29 ]. FDG-PET imaging takes advantage of these changes for both myeloma patient care and translational myeloma research using laboratory mice [ 30 ].…”

Plasma cell survival: The intrinsic drivers, migratory signals, and extrinsic regulators

“…This regulation has implications in the rapid and transient transcriptional suppression that leads to the profound and complex cellular changes during ASC generation and maturation. One class of such modulators is microRNAs (miRNA) which include miR‐155 and miR‐148a 81‐85 . Another class is RNA‐binding proteins (RBP).…”

MicroRNA regulation of B cell receptor signaling

“…As noted by the authors, miR-148 expression coincides with upregulation of Blimp-1 and helps reinforce plasma cell differentiation via repression of GC transcription factors Bach2 and Mitf, along with reducing expression of proapoptotic proteins BIM and PTEN. 110,112,113 NZB/WF1 strain is a murine lupus model in which females are more biased to disease, mimicking the known sex bias in lupus patients. 101 To explore sex-driven differences in miRNA expression, a TaqMan miRNA assay system was employed to compare miRNA expression between male and female NZB/WF1 splenocytes.…”