@article{05292f9ace2c4f8c8b79399b0f65f193,
title = "Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis",
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.",
keywords = "Langerhans cell, Mas-related G protein receptors, MrgprB2, MrgprD, S. aureus, beta-alanine, glutamate, kainate receptors, mast cell, neuroimmunology, nonpeptidergic neurons, skin",
author = "Shiqun Zhang and Edwards, {Tara N.} and Chaudhri, {Virendra K.} and Jianing Wu and Cohen, {Jonathan A.} and Toshiro Hirai and Natalie Rittenhouse and Schmitz, {Elizabeth G.} and Zhou, {Paul Yifan} and McNeil, {Benjamin D.} and Yi Yang and Koerber, {H. Richard} and Sumpter, {Tina L.} and Poholek, {Amanda C.} and Davis, {Brian M.} and Albers, {Kathryn M.} and Harinder Singh and Kaplan, {Daniel H.}",
note = "Funding Information: We thank Dr. Sarah Ross as well as other members of the University of Pittsburgh Center for Pain Research and Departments of Dermatology and Immunology for helpful discussions. We also thank the Division of Laboratory Animal Resources of the University of Pittsburgh for excellent animal care, Will MacDonald at the Health Sciences Sequencing Core at Children{\textquoteright}s Hospital of Pittsburgh for RNA-seq, and the Flow Cytometry core for cell sorting. This work benefitted from SPECIAL BD LSRFORTESSATM funded by National Institutes of Health (NIH) grant 1S10OD011925-01 . This work was supported by grants from the National Eczema Association (D.H.K.) and NIH grants R01AR071720 (D.H.K. and K.M.A.), R01NS096705 (H.R.K.), and R01AR077341 (D.H.K., V.K.C., H.S., and K.M.A.). Funding Information: We thank Dr. Sarah Ross as well as other members of the University of Pittsburgh Center for Pain Research and Departments of Dermatology and Immunology for helpful discussions. We also thank the Division of Laboratory Animal Resources of the University of Pittsburgh for excellent animal care, Will MacDonald at the Health Sciences Sequencing Core at Children's Hospital of Pittsburgh for RNA-seq, and the Flow Cytometry core for cell sorting. This work benefitted from SPECIAL BD LSRFORTESSATM funded by National Institutes of Health (NIH) grant 1S10OD011925-01. This work was supported by grants from the National Eczema Association (D.H.K.) and NIH grants R01AR071720 (D.H.K. and K.M.A.), R01NS096705 (H.R.K.), and R01AR077341 (D.H.K. V.K.C. H.S. and K.M.A.). S.Z. H.S. and D.H.K. designed and interpreted experiments; S.Z. T.N.E. J.W. J.A.C. T.H. and Y.Y. performed experiments; N.R. E.G.S. P.Y.Z. V.K.C. and H.S. designed conducted and interpreted the bioinformatics analyses; B.D.M. H.R.K. T.L.S. A.C.P. B.M.D. and K.M.A. provided technical and conceptual assistance; S.Z. H.S. and D.H.K. wrote the manuscript, and all authors edited it. D.H.K. has a patent pending for the use of ?-ala to suppress MC activation in disease states. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "15",
doi = "10.1016/j.cell.2021.03.002",
language = "English (US)",
volume = "184",
pages = "2151--2166.e16",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "8",
}