Neuronal Control of Host Defense Against Bee Phospholipase A2

Abstract

Neuroimmune interactions have been increasingly recognized as key mechanisms in both promotion and modulation of mammalian host defense against external insults. In particular, skin-innervating TRPV1+ sensory neurons are known to directly detect harmful stimuli, including microbial products, toxins, and allergens, and respond by releasing neuropeptides, which signal to local innate immune cells to inform subsequent inflammatory, wound-healing, and/or adaptive immune responses. In this dissertation, I explore roles of sensory neurons in the allergic sensitization to bee venom allergen phospholipase A2 (bvPLA2) and in the innate host defense against its systemic toxicity. Using footpad injections in wildtype mice, I confirm that bvPLA2 induces a type-2 allergic immune response, mediated by CD301b+ skin dendritic cells (DCs) and characterized by development of Th2 cells in the draining lymph node (dLN) and production of IgE. We also report that bvPLA2 directly activates dorsal root ganglia neurons, evidenced by release of the neuropeptide CGRP both in vitro and in vivo. Utilizing two methods of in vivo TRPV1+ neuron ablation, I show that TRPV1+ neurons dampen the migration of activated CD301b+ DCs in response to subcutaneous bvPLA2 immunization via a CGRP-independent mechanism and limit the subsequent development of Th2 cells in the dLN. Besides its allergenicity, bvPLA2 is also highly toxic due to its ability to disrupt cell membranes and contributes to multi-organ damage during mass envenomation events. Here I also describe a crucial protective role of TRPV1+ neurons against rapid and systemic toxic effects of bvPLA2, wherein ablation of TRPV1+ neurons renders mice highly susceptible to death within 24 hours after a single subcutaneous injection of bvPLA2 at a normally sublethal dose. I also characterize the early local innate immune response to bvPLA2 in the skin and investigate a possible link between TRPV1+ neurons and bvPLA2-induced eosinophil influx and degranulation. In summary, this thesis reports two distinct mechanisms through which TRPV1+ neurons control host defense responses to bvPLA2 as a venom toxin and allergen.