Sense and Immunity: Context-Dependent Neuro-Immune Interplay

Abstract

The sensory nervous and immune systems, historically considered autonomous, actually work in concert to promote host defense and tissue homeostasis. These systems interact with each other through a common language of cell surface G protein-coupled receptors and receptor tyrosine kinases as well as cytokines, growth factors, and neuropeptides. While this bidirectional communication is adaptive in many settings, helping protect from danger, it can also become maladaptive and contribute to disease pathophysiology. The fundamental logic of how, where, and when sensory neurons and immune cells contribute to either health or disease remains, however, unclear. Our lab and others' have begun to explore how this neuro-immune reciprocal dialog contributes to physiological and pathological immune responses and sensory disorders. The cumulative results collected so far indicate that there is an important role for nociceptors (noxious stimulus detecting sensory neurons) in driving immune responses, but that this is highly context dependent. To illustrate this concept, we present our findings in a model of airway inflammation, in which nociceptors seem to have major involvement in type 2 but not type 1 adaptive immunity.

Keywords: allergy and immunology; asthma; inflammation; neuro-immunological signaling; sensory neurons.

Figure 1

Nociceptor activation promotes Th2 but not Th1 airway inflammation. In the aluminum hydroxide (AlOH)/ovalbumin (OVA) sensitized mice (A–C), a standard model of airway Th2-driven inflammation, OVA-challenge do not significantly increase the numbers of ILC2 cells (A) in the lung but did enhance their production of IL-5 (B) as well as the numbers of inflammatory dendritic cells (DCs) in bronchoalveolar lavage fluid (BALF) (C). Silencing lung sensory neurons with aerosolized QX-314 (0.003%, 20 min nebulization, 20 psi) decreased these Th2 immune cell responses. By contrast, silencing nociceptors in a Th1-driven lung inflammation model [complete Freund’s adjuvant (CFA)]/OVA sensitized mice; (D–F), had no impact on the OVA-challenge induced increases in BALF CD3⁺ (D), eosinophils (E), and macrophages (F). Mean ± SEM; Two-tailed unpaired Welsh’s t-test (n = 5–12 animals/group; 1–2 cohorts).

Figure 2

Context-dependent neuro-immune interactions; nociceptors participate in Th2 but not Th1 type inflammation depending on the tissue type. Left panel. In type 2 inflammation, allergens or parasites are sensed by epithelial and dendritic cells (DCs). Epithelial cells may secrete mediators such as thymic stromal lymphopoietin (TSLP) which sensitize nociceptors. Nociceptors release neuropeptides including VIP which act on DCs and Th2 cells and contribute to their activation. Th2 cells secrete cytokines (IL-4 and IL-5) that both drive type 2 inflammation and act on nociceptors forming an inflammatory loop. While such inflammation perhaps aids in parasite clearance by promoting coughing and mucus secretion, if amplified and prolonged, this bidirectional communication contributes to the pathology of allergic inflammation. Right panel. The case is different in our model of Th1 type inflammation where the neuropeptides secreted by nociceptors do not activate immune cells and may even actively inhibit type 1 immunity. In this situation, nociceptors may sense pathogen-associated molecules and produce neuropeptides that limit DCs activation and downstream Th1 responses.