Allergen-induced dendritic cell migration is controlled through Substance P release by sensory neurons

Background

Allergic immune responses are a puzzling phenomenon: how to explain disproportionately aggressive inflammatory responses to (generally) innocuous substances? For years it was widely accepted that allergy was the result of the subversion of type-2 immune mechanisms that evolved to fight multicellular parasites. Currently, however, compelling evidence indicates that type-2 immunity not only provides protection to parasite infections but also to harmful environmental stimuli – in fact, it has been suggested that the unpleasant outcomes of an allergic reaction are a way of promoting the expulsion and future avoidance of the noxious agent that triggered it. Different immune cell populations, such as mast cells, dendritic cells (DCs) and T helper (Th) 2 cells, are key in the establishment of type-2 immune responses; yet, how these cells sense structurally diverse allergens is still unclear. For instance, mouse dermal CD301b+ DCs were shown to induce Th2 cell differentiation upon allergen exposure in vivo, but not in vitro. So, which other factors within the tissue might be assisting CD301b+ DCs? Here in this preprint Aderhold and colleagues show that sensory neurons in the skin recognize allergens and through Substance P (SP) production induce CD301b+ DCs migration to the lymph nodes (LN) and subsequent Th2 cell generation.

 

Key Findings

Allergens activate cutaneous sensory neurons promoting itch responses

In order to investigate the initial events occurring after allergen encounter, the authors used the well-defined model of intradermal injection of papain (a prototypical enzymatically active allergen). Mice challenged with papain showed transient itch and pain responses, which were dependent on papain’s intact enzymatic activity. Interestingly, even though mast cells have been shown to mediate sensory neuron activation after allergen exposure, papain injection in mast cell-deficient mice still triggered both itch and pain responses. On the other hand, chemical blockade of sodium channels present in neurons, such as TRPV1 and TRPA1, abrogated sensory response to papain. Accordingly, in vitro stimulation of neurons showed that a population of TRPV1+ neurons was able to respond directly to papain; and by using a genetic mouse model to ablate TRPV1-expressing cells, the authors demonstrated that sensory response to papain is, in fact, dependent on TRPV1+ neurons.

Neuronal activation upon allergen encounter licenses dendritic cell migration to lymph nodes

Apart from triggering sensory responses by TRPV1+ neurons, the authors observed that in vivo, but not in vitro, papain exposure induces activation and chemotactic activity on CD301b+ DCs. Furthermore, microscopy analysis of mouse skin showed that CD301b+ DCs are found in close proximity to sensory neurons, in contrast to other DC subsets. Thus, suggesting that papain recognition by neurons trigger DC activation and chemotaxis during allergic responses. In fact, chemical blockade of TRPV1 channels and genetic ablation of TRPV1+ cells resulted in a decrease in DC migration to the LN, after allergen exposure.

Dendritic cell activation by neurons is mediated by Substance P

SP is a neuropeptide produced by neuronal and immune cells both under physiological and inflammatory conditions. Allergen exposure was already shown to induce SP production by TRPV1+ neurons. Here, the authors show that in vitro stimulation of skin explants and neuronal cultures with papain also induces SP release. Accordingly, SP-deficient mice presented decreased numbers of activated CD301b+ DCs in the LN after papain challenge. Moreover, addition of SP during allergen immunization specifically enhanced the migration of CD301b+ DCs to LNs. Mast cells have been shown elsewhere to respond to neuron-derived SP, however mast cell-deficient mice showed similar numbers of activated DCs in the LN after allergen exposure when compared to their wild-type (WT) counterparts. Thus, suggesting that SP acts directly on DCs to stimulate their migration. In fact, the authors further support this hypothesis by showing that: i) Mrgpra1 (the gene encoding one of the SP receptors) is specifically expressed on LN CD301b+ DCs after allergen immunization; and ii) in vitro stimulation with SP induces chemotactic activity on WT, but not MRGPRA1-deficient, DCs.

Activation of cutaneous sensory neurons is required for optimal Th2 cell  differentiation

After antigen encounter in non-lymphoid tissues, DCs migrate to LN and promote T cell differentiation. Interestingly, the authors found that in TRPV1+ neuron-depleted mice there was a reduction in Th2 cells in the LN after allergen exposure. In addition, chemical blockade of TRPV1 channels or SP receptors also results in a decrease in Th2 cell differentiation. Of note, although SP alone induces DC migration to the LN it is not sufficient to induce Th2 cell generation, suggesting that other signals are required for DCs to be fully capable of stimulating T cells in the LN.

 

Relevance

It is becoming increasingly clear that the immune system does not act alone when initiating responses to environmental stimuli. In the present work, Aderhold and colleagues challenge the classical view of DCs acting as the primary sensor during  allergen exposure, and provide strong evidence that sensory neurons in the skin directly sense allergens and license dermal DCs to migrate to LN, where they, then, enhance type-2 immune responses. Even though neurons were already shown to be able to sense allergens and promote local inflammation, this report extends those findings to the cross-talk between neurons and CD103b+ DCs and subsequent generation of Th2 cells in the LNs. Finally, the data presented here open interesting questions regarding the role of neurons in controlling allergic responses.

 

Open Questions

• Could be neuron-derived SP a common feature of all type-2 immune responses initiated in the skin – including response to adjuvants without enzymatic activity, such as alum?
• Is the neuron – DC crosstalk also critical in the generation of Th2 responses after repeated epicutaneous exposure to innocuous antigens, such as OVA, in the absence of proteolytic agents?
• Does allergic sensitization promote changes in neuronal activation thresholds?
• With SP acting mainly on DC chemotaxis, what are the other signals that could endow CD301b+ DCs with the ability to promote Th2 responses? Are they also neuron-derived?

 

Tags: allergy, dendritic cells, neuroimmunology, th2, trpv1

doi: https://doi.org/10.1242/prelights.21995

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