NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells

Cell Commun Signal. 2014 Dec 5;12:75. doi: 10.1186/s12964-014-0075-5.

Abstract

Background: B cells are important effectors and regulators of adaptive and innate immune responses, inflammation and autoimmunity, for instance in anti-NMDA-receptor (NMDAR) encephalitis. Thus, pharmacological modulation of B-cell function could be an effective regimen in therapeutic strategies. Since the non-competitive NMDAR antagonist memantine is clinically applied to treat advanced Alzheimer`s disease and ketamine is supposed to improve the course of resistant depression, it is important to know how these drugs affect B-cell function.

Results: Non-competitive NMDAR antagonists impaired B-cell receptor (BCR)- and lipopolysaccharide (LPS)-induced B-cell proliferation, reduced B-cell migration towards the chemokines SDF-1α and CCL21 and downregulated IgM and IgG secretion. Mechanistically, these effects were mediated through a blockade of Kv1.3 and KCa3.1 potassium channels and resulted in an attenuated Ca(2+)-flux and activation of Erk1/2, Akt and NFATc1. Interestingly, NMDAR antagonist treatment increased the frequency of IL-10 producing B cells after BCR/CD40 stimulation.

Conclusions: Non-competitive NMDAR antagonists attenuate BCR and Toll-like receptor 4 (TLR4) B-cell signaling and effector function and can foster IL-10 production. Consequently, NMDAR antagonists may be useful to target B cells in autoimmune diseases or pathological systemic inflammation. The drugs' additional side effects on B cells should be considered in treatments of neuronal disorders with NMDAR antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • CD40 Antigens / metabolism
  • Cell Proliferation / drug effects
  • Immunoglobulin G / metabolism
  • Immunoglobulin M / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism
  • Kv1.3 Potassium Channel / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Piperidines / pharmacology*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Toll-Like Receptor 4 / metabolism

Substances

  • CD40 Antigens
  • Immunoglobulin G
  • Immunoglobulin M
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Kcnn4 protein, mouse
  • Kv1.3 Potassium Channel
  • Lipopolysaccharides
  • Piperidines
  • Receptors, Antigen, B-Cell
  • Receptors, N-Methyl-D-Aspartate
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Interleukin-10
  • Interferon-gamma
  • ifenprodil