Neuronal Regulation of Immunity in the Skin and Lungs

Abstract

The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma.

Keywords: asthma; inflammation; lungs; nervous system; neuroimmunology; skin.

Figure 1.. Neuronal interactions with immune cells in healthy skin and in dermatitis.

a) In healthy conditions, the epidermal layer is made of tightly spaced keratinocytes, which helps to keep allergens, pathogens, and microbial toxins out. Skin resident innate immune cells including dermal DCs (dDCs), γδ T cells, ILCs, and mast cells are ideally poised to respond to signals communicated by surrounding sensory nerve fibers. b) Allergic contact dermatitis (ACD) is a T-cell mediated, type-IV hypersensitivity reaction induced by allergens/haptens that results in itchy and inflamed skin. The nociceptive ion channel, TRPA1, was found to mediate both persistent itch and inflammation (edema, leukocyte infiltration, and keratinocyte hyperplasia) in mouse models of ACD driven by squaric acid dibutylester (SADBE), urushiol, or oxazolone [33,88]. Sensory nerves are thought to modulate the immune response by interacting with antigen presenting cells (APCs) in these conditions [32]. c) Atopic dermatitis (AD) is an allergic inflammatory skin condition that results in thickened scaly skin and impaired epidermal barrier function, allowing the penetration of allergens and microbial toxins into the skin. Activated sensory nerves promote neurogenic inflammation (b, c), and secrete substance P (SP), which leads to degranulation of mast cells (MC) that release histamine and other cytokines. This pruritogenic cocktail potentiates the itch-scratch cycle characteristic of AD and also helps to further recruit immune cells to the inflamed area (darkened area surrounding each keratinocyte). Nerves also release CGRP, which mediates keratinocyte hyperplasia, resulting in increased epidermal thickness (b, c) [37]. Keratinocytes also release NGF (not shown), which leads to neuronal hyper-innervation and penetration of the sensory nerves into the topmost layers of the skin, illustrated in the figure by the nerve endings (blue) extending through the spaces in between keratinocytes into the topmost layers of the epidermis.

Figure 2.. Neuroimmune interactions in skin infection and psoriasis.

Several pathogens, such as Candida albicans, Staphylococcus aureus, and Streptococcus pyogenes have been determined to interact with sensory nerves in the skin to drive neuro-immune modulation. Pathogenic activation of sensory nerves leads to release of neuropeptides that modulate immune cells during infection, affecting infection and disease outcome. a) The pathogenic yeast, C. albicans, activates sensory nerves during epicutaneous infection to release the neuropeptide CGRP, which augments the release of IL-23 from CD301b⁺ dermal dendritic cells (dDCs). IL-23 then drives IL-17 release from γδ T-cells, which mediates resistance against C. albicans due to induction of polymorphonuclear neutrophil (PMN) recruitment and expression of antimicrobial peptides (AMPs) [24]. In a mouse model of psoriasis, a similar neuroimmune interaction was found: sensory nerves mediate IL-23 release from dDCs which mediate IL-17 release by γδ T-cells that contribute to psoriatic inflammation and plaque formation [23]. A similar neuro-immune mechanism operates during psoriasis-like inflammation. b) S. pyogenes and S. aureus are two bacterial pathogens known to cause painful and invasive skin infections such as abscesses, cellulitis, and necrotizing fasciitis. These pathogens directly activate sensory nerves via pore-forming toxins to produce pain and to release CGRP from their nerve terminals. In S. pyogenes infection, CGRP prevents the recruitment of neutrophils (PMNs) and the subsequent killing of the bacteria, worsening the infection outcome and bacterial clearance [53]. In S. aureus infection, nociceptor release of CGRP decreases TNFα production from macrophages and lymph node hypertrophy, subsequently decreasing bacterial killing [50].

Figure 3.. Neuroimmune interactions in the lungs.

The lungs (center) are innervated by the parasympathetic, sympathetic, and sensory components of the peripheral nervous system. Parasympathetic nerves travel to the lungs via the vagus nerve, which originate in the medulla. Sympathetic nerves originate in the ventral horn of the spinal cord. Nociceptive sensory nerves either innervate the lungs via the vagus nerve from the nodose and jugular ganglia or from the dorsal root ganglion located in the spinal cord. Left: Lung-innervating nociceptor neurons can be activated by TRPV1 and/or TRPA1 stimulation in response to a variety of stimulants such as chemicals and irritants. Release of the neuropeptide calcitonin gene-related peptide (CGRP) can inhibit neutrophil recruitment and surveillance [14,86,89], whereas vasoactive intestinal peptide (VIP) activates ILC2s [64] and T_H2 cells [77]. T_H2 cells produce IL-5, which is a potent activator of eosinophils. Substance P (SP) binds to mas-related G-protein coupled receptor member B2 (MrgprB2) on mouse mast cells [44], resulting in their degranulation and thus the release of histamine and other cytokines. Right: Lung-innervating autonomic neurons modulate ILC2 function. Parasympathetic nerves release neuromedin U (NMU) which acts on NMU receptor 1 (NMUR1) expressed on type 2 innate lymphoid cells (ILC2s) to trigger release of interleukin 5 (IL-5) and interleukin 13 (IL-13). IL-5 and IL-13 can then act on goblet cells to promote mucus release [3,65,66]. Noradrenaline (NA) release from sympathetic nerves, which binds to β2-adrenoreceptor (ADRB2) on ILC2s, inhibits the release of these cytokines [67,68].