Abstract
Neuroimmune interactions are important in the pathophysiology of many chronic inflammatory diseases, particularly those associated with alterations in sensory processing and pain. Mast cells and sensory neuron nerve endings are found in areas of the body exposed to the external environment, both are specialized to sense potential damage by injury or pathogens and signal to the immune system and nervous system, respectively, to elicit protective responses. Cell adhesion molecule 1 (CADM1), also known as SynCAM1, has previously been identified as an adhesion molecule which may couple mast cells to sensory neurons however, whether this molecule exerts a functional as well as structural role in neuroimmune cross-talk is unknown. Here we show, using a newly developed in vitro co-culture system consisting of murine bone marrow derived mast cells (BMMC) and adult sensory neurons isolated from dorsal root ganglions (DRG), that CADM1 is expressed in mast cells and adult sensory neurons and mediates strong adhesion between the two cell types. Non-neuronal cells in the DRG cultures did not express CADM1, and mast cells did not adhere to them. The interaction of BMMCs with sensory neurons was found to induce mast cell degranulation and IL-6 secretion and to enhance responses to antigen stimulation and activation of FcεRI receptors. Secretion of TNFα in contrast was not affected, nor was secretion evoked by compound 48/80. Co-cultures of BMMCs with HEK 293 cells, which also express CADM1, while also leading to adhesion did not replicate the effects of sensory neurons on mast cells, indicative of a neuron-specific interaction. Application of a CADM1 blocking peptide or knockdown of CADM1 in BMMCs significantly decreased BMMC attachment to sensory neurites and abolished the enhanced secretory responses of mast cells. In conclusion, CADM1 is necessary and sufficient to drive mast cell-sensory neuron adhesion and promote the development of a microenvironment in which neurons enhance mast cell responsiveness to antigen, this interaction could explain why the incidence of painful neuroinflammatory disorders such as irritable bowel syndrome (IBS) are increased in atopic patients.
Highlights
Mast cells are best known for their role in allergic diseases
As a prelude to understanding the role that cell adhesion plays in regulating mast cell-sensory neuron interactions, we established a co-culture system of C57BL6 mouse bone marrow derived mast cells (BMMC) and primary dorsal root ganglions (DRG) neurons isolated from adult mice (8–12 weeks)
Immunocytochemistry of DRGs maintained in mono-culture for 48 h with the neuronal marker β-tubulin confirmed the expression of Cell adhesion molecule 1 (CADM1) was specific to neurons and notably absent from non-neuronal glialike cells which surrounding the neurons, whose presence can be detected from DAPI staining of their nuclei (Figures 1D,E)
Summary
The symptoms of allergic reactions are instigated by the secretion of a plethora of pro-inflammatory mediators from mast cells following antigen-dependent crosslinking of IgE receptors (FcεRI) (Galli and Tsai, 2012). These mediators include preformed molecules stored in granules such as histamine, serotonin, adenosine 5 -triphosphate (ATP), proteases, tumor necrosis factor-α (TNFα), chemokines, and peptides, as well as de novo synthesized cytokines, growth factors and lipid mediators (Sismanopoulos et al, 2012). Knowledge of the adhesion molecules regulating mast-cell sensory neuron contacts may provide new insight into disease mechanisms and strategies for intervention
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