TRPV1+ Neurons are Required for Antigen‐Specific Immune Responses

Abstract

The lung is densely innervated by sensory neurons expressing nociceptors including transient receptor potential vanilloid channel 1 (TRPV1+). Nociceptors detect and respond to pathogen-associated molecular patterns and other inflammatory mediators. However, the function of nociceptors in regulating lung antigen-specific immune responses is unknown. Here, using chemogenetic mice we reveal sensory nociceptor fibers expressing TRPV1+ are required for efficient antigen-specific immune responses. Chemogenetics enable temporal control of neuron activity using Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Inhibitory G protein (Gi-DREADD) is a modified muscarinic acetylcholine receptor that binds the ligand, clozapine-N-oxide (CNO), which triggers inhibitory G protein signaling to inhibit neuronal excitability. To selectively silence TRPV1+ nociceptors, we generated TRPV1-Gi-DREADD mice to transiently inhibit neuronal activity specifically in TRPV1+ neurons. CNO or Vehicle was administered intraperitoneally to TRPV1-Gi-DREADD mice 30 minutes prior to intratracheal immunization with 4-Hydroxy-3-nitrophenylacetyl hapten coupled to ovalbumin (NP27-OVA). Chemogenetic inhibition of TRPV1+ neurons, before primary immunization, significantly diminishes NP-specific antibody responses. We observe a significant reduction in NP-specific IgG in mice receiving CNO as compared to vehicle controls at 14 days post-immunization (Anti-NP IgG1 U/mL, Mean ± SEM, D14: vehicle, 120,877 ± 29,519, n=10 versus CNO, 42,525 ± 14,641, n=11, ** p=0.0017). These results indicate TRPV1+ sensory neurons are required to initiate primary antibody responses to novel antigens. These findings offer significant new insights into the biological mechanisms of vaccination.