Nonpeptidergic neurons suppress cutaneous inflammation via glutamate release

/ABSTRACT Rosacea is an inflammatory disorder of the skin that manifests with chronic symptoms including pruritus (itch), rash, and flushing and contributes significantly to patient morbidity. The prevalence of rosacea is estimated to be as high as 20% in some populations. Mast cell activation and degranulation is a key mediator of rosacea symptoms. A growing body of evidence has demonstrated that cutaneous sensory neurons and skin-resident immune cells including mast cells work synergistically to promote local inflammation. For example, pain sensing Trpv1-expressing neurons release the neuropeptide Substance P which activates dermal mast cells via the MrgprB2 receptor. Our recent work has explored the role of a distinct subset of sensory neurons innervating the epidermis, classified as nonpeptidergic type 1 neurons (NP1). In contrast to the mast cell activating capacity of Trpv1 neurons, NP1 neurons suppress mast cell function through the release of the neurotransmitter glutamate which acts directly on mast cells via the kainate receptor GluK2. We have recently found that β-alanine, a known ligand of the NP1 mas related G-protein-coupled receptor D (Mrgprd) that triggers glutamate release, and the small molecule GluK2 receptor agonist SYM2081 both suppressed mast cell-induced inflammation in models of rosacea. Remarkably, in preliminary clinical studies, we have discovered that topical administration of β-alanine suppresses rosacea flushing. Thus, we have discovered a novel neuron-mast cell circuit that regulates cutaneous inflammation. Upon further investigation of this pathway, we have found that abrogation of glutamate release from NP1 neurons augments clearance of epicutaneous Candida albicans infection (a model that is generally thought to be dependent on T cells and not mast cells). Conversely topical SYM2081 treatment induces broad transcriptional changes in multiple immune subsets in the skin. Taken together, our data predicts that NP1-derived glutamate, through its action on mast cells, has broader effects on cutaneous immunity than previously appreciated. We hypothesize that NP1-neuron derived glutamate regulates the responsiveness of mast cells at steady state which subsequently determines the composition of immune cells and functional immune responses in the skin. This proposal will investigate this pathway using transgenic mice that enable us to simulate conditions of low glutamate via the conditional ablation of glutamate release from NP1 neurons (Aim 1) as well as conditions of increased glutamate using direct small molecule agonism of the GluK2 receptor on mast cells (Aim 2). Findings from these studies will provide a mechanistic understanding of how NP1 neurons regulate immunity in the skin. Data generated from this study will have direct clinically translational impact in the treatment of rosacea and other cutaneous inflammatory processes. Contribution to Training: This proposal combines rigorous training in neurogenic inflammation and clinical medicine which will greatly enhance my ability to develop into a highly productive academic physician-scientist. Project Number: 1F30AI197374-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Colton Smith | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $55,114 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F07B-G (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F30AI19737401