Jiaci

Kuruvilla M, et al.

J Investig Allergol Clin Immunol 2019; Vol. 29(5): 349-356

doi: 10.18176/jiaci.0320

Ocular Symptoms Deriving From

Neurogenic Inflammation

The importance of neurogenic inflammation is suggested

by the large trigeminal sensory innervation of the ocular

surface. Mast cell activation inAC results in overt stimulation

of polymodal nociceptors, which are responsible for burning

and stinging eye pain. Nasal provocation studies in AR

patients showed that TRPV1 and TRPA1 activators induced

immediate and more prolonged pain; during the pollen

season, provocations with TRPV1 activators induced itch as

well as pain [33]. In fact, in a recent series, 80% of patients

with symptomatic AC had no evidence of conjunctival

inflammation, while over half had nasal inflammation only. It

was postulated that neurogenic mediators could explain this

disconnect between ocular symptoms (especially itching) and

detectable inflammatory conjunctival infiltration [34].

Emerging evidence suggests that the underlying allergic

and neural inflammatory pathways can interact. Histamine-

induced itching via H1 receptors on conjunctival sensory nerve

fibers requires activation of TRPV1. Histamine-independent

pruritic pathways, as in IL-31–induced itch, also directly

activate TRPV1/TRPA1 sensory nerves in mouse models

of dermatitis [35]. Furthermore, leukotriene B4 (LTB4) can

activate TRPV1 and induce itching via interaction with LTB4

receptors on sensory nerves [36].

The activation of TRPV1 causes the release of

proinflammatory and pruritic mediators. It has been reported

that substance P levels are increased in tears of patients

with AC compared with healthy individuals, suggesting that

substance P may contribute to the pathogenesis and severity

of AC [37]. The concentration of substance P in tears has also

been found to be elevated at baseline in patients with seasonal

AC and vernal keratoconjunctivitis [38], with further increases

in substance P and CGRP documented after conjunctival

allergen challenge [39]. On the ocular surface, NGF has been

hypothesized to influence the immune response in AC [40].

A strong relationship has long been recognized between

AC and dry eye, with a large symptomatic crossover that

may reflect interrelated mechanistic characteristics [41]. Tear

film instability, a characteristic of dry eye, was also noted

to be more pronounced in children with AC [42]. Increased

inflammatory allergic cytokines are also associated with goblet

cell loss and tear volume insufficiency. Recent evidence has

further expanded the phenotypic spectrum of patients with

dry eye syndrome and implicated neuropathic pain in dry

eye pathogenesis. A significant body of physiological data

suggests that dry eye symptoms may be significantly modulated

by the nervous system [43]. However, our understanding

of neuropathic pain in dry eye remains incomplete, largely

because of limited access to tests that assess the function of

the ocular sensory-nociceptive apparatus.

Neurogenic Mechanisms of AC:

Implications for Management Approaches

The current mainstay of AC therapy includes topical

mast cell stabilizers and antihistamines, with variable and

limited clinical success possibly because factors other

than mast cells and histamine play important roles in

AC. Therefore, research into more effective treatments

is necessary. The simultaneous targeting of multiple

inflammatory signaling mediators might represent a more

promising treatment modality.

Addressing the neurogenic component of allergic

inflammation has been an active area of study. The

hyperreactivity phenotype of allergic sensitization can be

physiologically dissociated from the immune component,

and neural sensitization has been targeted in animal models

as well as in humans.

Murine models of allergic sensitization have provided

evidence of the anti-inflammatory actions induced

by the depletion of neuropeptides [25]. Mice that had

undergone surgical denervation of cutaneous sensory

nerves demonstrated dampened inflammatory responses

after induction of anaphylaxis and mast cell activation.

Similar responses were obtained following pretreatment with

selective substance P and CGRP antagonists [44]. Recently,

treatment with olopatadine and naphazoline hydrochloride

was shown to reduce conjunctivitis in mice via effects on

NGF [45].

A prominent candidate pathway is TRPV1, which has

been described in several forms of allergic disease. Vagal

sensory neurons in TRPV1 can dramatically affect airway

hyperreactivity. Several trials have explored therapies that

target TRPV1-expressing neurons as a strategy for the

management of allergic diseases. This has been supported

by murine models, where ablation of TRPV1 expressing

vagal neurons abolishes airway hyperreactivity, even in

the presence of a full lung inflammatory response [46]. In

yet another mouse model, the use of a TRPV1 antagonist

alleviated atopic dermatitis–like symptoms as evidenced by

suppression of itch behavior and acceleration of skin barrier

recovery [47]. In another murine model of AC, ocular itch

was significantly attenuated in TRPA1 and TRPV1 knockout

mice, implicating both TRPA1 and TRPV1 in the genesis of

allergic ocular itch [48].

Clinical trials exploring the potential for neuronal-targeted

therapies in patients with allergic inflammation are in their

early stages. However, in subjects with allergic rhinitis,

an intranasal TRPV1 antagonist alone or combined with

fluticasone propionate did not improve allergen-induced

symptoms [49]. Similarly, symptoms appearing after exposure

to cold dry air in patients with nonallergic rhinitis did not

Improve with this therapy [50].

These findings may indicate that TRPV1 may be a

facilitating ion channel—but not a key mediator—for itch

and other allergic symptoms, suggesting that other receptors

expressed in C fibers, such as TRPA1, might be involved in

their development.

On the other hand, a recent study of patients with

nonallergic rhinitis revealed overexpression of TRPV1 in

the nasal mucosa and increased substance P levels in nasal

secretions at baseline, with reduced symptoms and reduced

levels of nasal hyperreactivity following topical capsaicin

treatment [19]. The authors suggest that the ablation of

the TRPV1–substance P nociceptive signaling pathway

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