Asthmatic LGE release is due to substance P released by sensory neurons

The National Institute of Allergy and Infectious Diseases awarded the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center $245,250 on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate how sensory neuron release of substance P stimulates B cell immunoglobulin E production in asthma.

The research will examine the mechanism by which the neuropeptide substance P, released from neurons sensitized during asthmatic inflammation, drives B cell fate, maturation, and class switch recombination to IgE overproduction. Preliminary data demonstrates that substance P is preferentially released in response to Alternaria alternata induction of asthma in mice, that sensory neuron depletion reduces both substance P and IgE production, and that substance P knockout mice produce less IgE than wild-type littermates. The investigator will test the hypothesis that substance P binds to MRGPRA1 receptors on B cells to control transcription factors steering cell fate and class switch recombination in two research aims.

The award carries a period of performance from July 1, 2026, through June 30, 2028. Work is performed at the recipient's Torrance, California location. This is a project grant assistance type under the NIH competitive grant mechanism, supporting investigator-initiated research in infectious disease and allergic disease within the NIH portfolio.

Abstract

Asthma and asthmatic symptoms continue to pose a significant health burden to the USA, demonstrating the need to understand how the primary asthmatic effector molecule, immunoglobulin (IG) E (IGE), is produced. While IGE production can lead to protective immunity in response to venoms and multicellular pathogens, its overproduction in response to benign substances underlies its role in asthmatic inflammation. IGE is secreted from B lineage cells in the presence of cognate antigen and activates mast cells and basophils to release potent inflammatory molecules that act directly on the airway wall and attract inflammatory cells to the lungs. Emerging evidence demonstrates that asthmatic inflammation sensitizes another cell type, neurons. Once sensitized, neurons release a host of neuropeptides that enhance asthmatic inflammation. This application aims to investigate how the release of neuropeptides from sensory neurons drives B cell fate, maturation, and class switch recombination to IGE. The overall objective of this application is to investigate how sensory neuron release of the neuropeptide substance P stimulates B cell IGE release in asthma. Our preliminary work shows that substance P is preferentially released in response to alternaria alternata induction of asthma in mice and that sensory neuron depletion reduces substance P release and IGE production. Supplementation of substance P back into the lungs of sensory neuron-ablated mice restores the asthmatic phenotype. Also, substance P knockout mice (those that do not produce substance P) produce less IGE in response to a alternata compared to WT littermates. This occurs via substance P binding to MRGPRA1 receptors on B cells and ultimately controls transcription factors to steer cell fate, maturation, and class switch recombination. We will investigate this novel mechanism of IGE overproduction in two aims. Aim 1 will test how substance P regulates B cell class switch recombination via specific transcriptional regulation in vitro with protein analysis, flow cytometry, and IGE germline and circular transcripts. In addition, the asthmatic phenotype in vitro using murine and human B cells and in vivo using adoptive transfer techniques. Aim 2 will investigate the maturation of B cells induced by substance P using in vitro and in vivo protein analysis and flow cytometry. This contribution is significant because IT is expected to elucidate how integrated neuroimmune regulation augments IGE production and dysregulation in asthma. Such knowledge can inform the development of new strategies that will help reduce the growing problem of chronic asthmatic disease, directly in line with the mission statement of the NIH, to reduce the burden of human disease.