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

Abstract

BackgroundB 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.ResultsNon-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 Ca2+-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.ConclusionsNon-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.

MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease

“…15 Interestingly, the noncompetitive N-methyl-D-aspartate receptor antagonist, memantine, also attenuates adaptive as well as innate B cell signaling and may be useful to target B cells under pathological inflammatory conditions like AD. 16 MEF2C is also reported to be a central transcriptional component of the innate immune response. 45 In the adult human brain, MEF2C is highly expressed in brain regions involved in learning and memory, such as the frontal cortex, entorhinal cortex, dentate gyrus, and amygdala.…”

“…14 MEF2C enhances the expression of DNA repair molecules and recombination factors in B-cell progenitors and promotes cell survival. 15 A non-competitive N-methyl-D-aspartate receptor antagonist, memantine, reduces B-cell proliferation 16 and is used to treat the symptoms of AD. These data suggest the presence of a relation between B cell immunological responses and AD.…”

Micro RNA-98 suppresses interleukin-10 in peripheral B cells in patient post-cardio transplantation

“…By employing an established cell culture model [17], we were able to up regulate IL-10 expression in B cells. Peripheral B cells were isolated from blood samples collected from healthy subjects.…”

Duality of Antidepressants and Neuroprotectants

“…Antidepressant effects of ketamine may also be due to its suppression of pro-inflammatory cytokines such as TNF-α and IL-6 (Taniguchi et al 2001, 2004) and promoting the activity of anti-inflammatory cytokines such as IL-10 (Simma et al 2013). Ketamine may also suppress the expression of pro-inflammatory cytokines induced by lipopolysaccharide (LPS), an exotoxin derived from the outer membrane of Gram-negative bacteria (Helmer et al 2003a, b; Chang et al 2009; Yang et al 2013a).…”