{Reference Type}: Journal Article
{Title}: Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.
{Author}: Zhang S;Edwards TN;Chaudhri VK;Wu J;Cohen JA;Hirai T;Rittenhouse N;Schmitz EG;Zhou PY;McNeil BD;Yang Y;Koerber HR;Sumpter TL;Poholek AC;Davis BM;Albers KM;Singh H;Kaplan DH;
{Journal}: Cell
{Volume}: 184
{Issue}: 8
{Year}: 04 2021 15
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2021.03.002
{Abstract}: Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.