ABSTRACT
The interaction between the sympathetic nervous system and the immune system has been documented over the last several decades. In this review, the neuroanatomical, cellular, and molecular evidence for neuroimmune regulation in the maintenance of immune homeostasis will be discussed, as well as the potential impact of neuroimmune dysregulation in health and disease.
Subject(s)
Asthma/genetics , Immune System/metabolism , Pneumonia, Bacterial/genetics , Spinal Cord Injuries/genetics , Sympathetic Nervous System/immunology , Asthma/immunology , Asthma/metabolism , Asthma/pathology , Cytokines/genetics , Cytokines/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dendritic Cells/pathology , Gene Expression Regulation , Homeostasis/genetics , Homeostasis/immunology , Humans , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/pathology , Norepinephrine/genetics , Norepinephrine/immunology , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/metabolism , Pneumonia, Bacterial/pathology , Receptors, Adrenergic, beta-2/genetics , Receptors, Adrenergic, beta-2/immunology , Signal Transduction , Spinal Cord Injuries/immunology , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathology , Stress, PhysiologicalABSTRACT
Soluble CD23 plays a role in the positive regulation of an IgE response. Engagement of the ß2 adrenergic receptor (ß2AR) on a B cell is known to enhance the level of both soluble CD23 and IgE, although the mechanism by which this occurs is not completely understood. In this study, we report that, in comparison with a CD40 ligand/IL-4-primed murine B cell alone, ß2AR engagement on a primed B cell increased gene expression of a disintegrin and metalloproteinase (ADAM)10, which is the primary sheddase of CD23, as well as protein expression of both CD23 and ADAM10, in a protein kinase A- and p38 MAPK-dependent manner, and promoted the localization of these proteins to exosomes as early as 2 d after priming, as determined by both Western blot and flow cytometry and confirmed by electron microscopy. In comparison with isolated exosomes released from primed B cells alone, the transfer of exosomes released from ß2AR agonist-exposed primed B cells to cultures of recipient primed B cells resulted in an increase in the level of IgE produced per cell, without affecting the number of cells producing IgE, as determined by ELISPOT. These effects still occurred when a ß2AR antagonist was added along with the transfer to block residual agonist, and they failed to occur when exosomes were isolated from ß2AR-deficient B cells. These findings suggest that the mechanism responsible for mediating the ß2AR-induced increase in IgE involves a shuttling of the ß2AR-induced increase in CD23 and ADAM10 proteins to exosomes that subsequently mediate an increase in IgE.
Subject(s)
ADAM Proteins/metabolism , Amyloid Precursor Protein Secretases/metabolism , B-Lymphocytes/immunology , Exosomes/metabolism , Immunoglobulin E/metabolism , Membrane Proteins/metabolism , Receptors, IgE/metabolism , ADAM Proteins/genetics , ADAM10 Protein , Adrenergic beta-2 Receptor Agonists/pharmacology , Amyloid Precursor Protein Secretases/genetics , Animals , B-Lymphocytes/drug effects , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Immunoglobulin E/genetics , Immunoglobulin E/immunology , Lymphocyte Activation/drug effects , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Knockout , Protein Transport , Receptors, Adrenergic, beta-2/genetics , Receptors, Adrenergic, beta-2/immunology , Receptors, IgE/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The voltage-gated K(+) channel Kv1.3 has been reported to regulate transmitter release in select central and peripheral neurons. In this study, we evaluated its role at the synapse between visceral sensory afferents and secondary neurons in the nucleus of the solitary tract (NTS). We identified mRNA and protein for Kv1.3 in rat nodose ganglia using RT-PCR and Western blot analysis. In immunohistochemical experiments, anti-Kv1.3 immunoreactivity was very strong in internal organelles in the soma of nodose neurons with a weaker distribution near the plasma membrane. Anti-Kv1.3 was also identified in the axonal branches that project centrally, including their presynaptic terminals in the medial and commissural NTS. In current-clamp experiments, margatoxin (MgTx), a high-affinity blocker of Kv1.3, produced an increase in action potential duration in C-type but not A- or Ah-type neurons. To evaluate the role of Kv1.3 at the presynaptic terminal, we examined the effect of MgTx on tract evoked monosynaptic excitatory postsynaptic currents (EPSCs) in brain slices of the NTS. MgTx increased the amplitude of evoked EPSCs in a subset of neurons, with the major increase occurring during the first stimuli in a 20-Hz train. These data, together with the results from somal recordings, support the hypothesis that Kv1.3 regulates the duration of the action potential in the presynaptic terminal of C fibers, limiting transmitter release to the postsynaptic cell.
