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.
Subject(s)
B-Lymphocytes/drug effects , Interleukin-10/metabolism , Piperidines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Apoptosis/drug effects , B-Lymphocytes/metabolism , CD40 Antigens/metabolism , Cell Proliferation/drug effects , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Interferon-gamma/metabolism , Interleukin-10/genetics , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Kv1.3 Potassium Channel/metabolism , Lipopolysaccharides/pharmacology , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, B-Cell/metabolism , Toll-Like Receptor 4/metabolismABSTRACT
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca(2+) mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.
Subject(s)
Immune Tolerance/drug effects , Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Kv1.3 Potassium Channel/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , Interferon-gamma/metabolism , Interleukins/metabolism , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Kv1.3 Potassium Channel/metabolism , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , NFATC Transcription Factors/metabolism , Nerve Tissue Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Antigen, T-Cell/metabolism , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
Ligation of the BCR induces a complex signaling network that involves activation of Akt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca(2+) -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-κB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1α was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homo-zygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function.
