Neuroimmune interplay during type 2 inflammation: Symptoms, mechanisms, and therapeutic targets in atopic diseases

Abstract

Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation.

Keywords: Type 2 inflammation; asthma; atopic dermatitis; chronic rhinosinusitis with nasal polyposis; cytokines; eosinophilic esophagitis; neuroimmune; neuropeptides; prurigo nodularis; sensory neurons.

FIG 1.

Sensory pathologies in atopic diseases.

FIG 2.

Type 2 inflammation and sensory neurons: bidirectional cross talk. Stimulated neurons produce neuropeptides that can modulate the activity of immune cells, including the production of inflammatory mediators that can directly affect sensory neurons. IL-13Rα1, IL-13 receptor-α 1; IL-31RA, IL-31 receptor A; IL-33R, IL-33 receptor; MrgprCr11, Mas-related family of G protein-coupled receptor 11; MRGPRX1, Mas-related family of G protein-coupled receptor X1; Na_v, voltage-gated sodium channel; NMU, neuromedin U; PAR2, protease activated receptor 2; TSLPR, thymic stromal lymphopoietin receptor.

FIG 3.

Neuroimmune mechanisms underlying sensory pathologies in conditions associated with type 2 inflammation. *Depicted epidermal disruption pertains only to AD. ACh, Acetylcholine; ASM, airway smooth muscle.

FIG 4.

Biologics that inhibit type 2 inflammation. βc, β-chain; γc, γ-chain; ABPA, allergic bronchopulmonary aspergillosis; ADCC, antibody-dependent cellular cytotoxicity; AFR, allergic fungal rhinosinusitis; BP, bullous pemphigoid; CCL17, C-C motif chemokine ligand 17; CIU, chronic idiopathic urticaria; COPD, chronic obstructive pulmonary disorder; CRSsNP, chronic rhinosinusitis without nasal polyps; CSU, chronic spontaneous urticaria; EGPA, eosinophilic granulomatosis with polyangiitis; F_ENO, fractional exhaled nitric oxide; HES, hypereosinophilic syndrome; IL-1RαP, IL-1 receptor-α P; IL-5Rα, IL-5 receptor-α; IL-13Rα1/2, IL-13 receptor-α1/2; IL-31RA, IL-31 receptor A; IL-33R, IL-33 receptor; ILC, innate lymphoid cell; MCP-4, monocyte chemoattractant protein-4; mIgE, membrane IgE; NP, nasal polyps; OSMRβ, oncostatin-M specific receptor subunit beta; PC₂₀, provocative concentration causing a 20% drop in forced expiratory volume in 1 second from baseline; TSLPR, thymic stromal lymphopoietin receptor. Figure adapted with permission from Haddad EB et al.