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

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. 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. Type 2 immunity is a specialized, evolutionarily conserved arm of the immune system that combats ectoparasitic and endoparasitic helminths, expels toxins, and promotes tissue repair.1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers of type 2 inflammation in disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar, 2Gandhi N.A. Pirozzi G. Graham N.M. 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Collectively, these cells orchestrate a polarized type 2 immune response through type 2 cytokines, histamine, and other mediators that neutralize and expel parasitic helminths and toxins and repair the barrier through epithelial turnover, remodeling, and fibrosis. Although these processes are protective and intended to restore tissue homeostasis, in the setting of allergy and continuous barrier stress they become pathologic, resulting in a variety of chronic inflammatory diseases. Mechanical reflexes such as scratching, airway constriction, coughing, sneezing, and gastrointestinal motility also protect barrier surfaces and are triggered by direct activation of sensory neurons, often in concert with autonomic input to the target organs. Many of these manifestations are pathologically altered in diseases with type 2 immune dysregulation (Fig 1), including (but not limited to) atopic dermatitis (AD), prurigo nodularis (PN), asthma, food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), and eosinophilic esophagitis (EoE).1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers of type 2 inflammation in disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar,2Gandhi N.A. Pirozzi G. Graham N.M. Commonality of the IL-4/IL-13 pathway in atopic diseases.Expert Rev Clin Immunol. 2017; 13: 425-437Crossref PubMed Scopus (276) Google Scholar,5Hamilton J.D. Harel S. Swanson B.N. Brian W. Chen Z. Rice M.S. et al.Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.Clin Exp Allergy. 2021; 51: 915-931Crossref PubMed Scopus (59) Google Scholar,6Le Floc'h A. Allinne J. Nagashima K. Scott G. Birchard D. 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Histamine-containing mast cells and their relationship to NGFr-immunoreactive nerves in prurigo nodularis: a reappraisal.J Cutan Pathol. 1998; 25: 189-198Crossref PubMed Scopus (49) Google Scholar•Type 2 cytokines and OSM promote pruritogen sensitization9Sonkoly E. Muller A. Lauerma A.I. Pivarcsi A. Soto H. Kemeny L. et al.IL-31: a new link between T cells and pruritus in atopic skin inflammation.J Allergy Clin Immunol. 2006; 117: 411-417Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar•Neuropeptide release from sensory neurons induces proinflammatory cytokines and activates immune cells (eg, mast cells, basophils)7Kulka M. Sheen C.H. Tancowny B.P. Grammer L.C. Schleimer R.P. Neuropeptides activate human mast cell degranulation and chemokine production.Immunology. 2008; 123: 398-410Crossref PubMed Scopus (340) Google Scholar,8Liang Y. Marcusson J.A. Jacobi H.H. Haak-Frendscho M. Johansson O. Histamine-containing mast cells and their relationship to NGFr-immunoreactive nerves in prurigo nodularis: a reappraisal.J Cutan Pathol. 1998; 25: 189-198Crossref PubMed Scopus (49) Google Scholar,10Tominaga M. Takamori K. Peripheral itch sensitization in atopic dermatitis.Allergol Int. 2022; 71: 265-277Crossref Scopus (19) Google Scholar, 11Garcovich S. Maurelli M. Gisondi P. Peris K. Yosipovitch G. Girolomoni G. Pruritus as a distinctive feature of type 2 inflammation.Vaccines (Basel). 2021; 9: 303Crossref PubMed Scopus (50) Google Scholar, 12Kim Y.J. Granstein R.D. Roles of calcitonin gene-related peptide in the skin, and other physiological and pathophysiological functions.Brain Behav Immun Health. 2021; 18100361PubMed Google Scholar, 13Wang F. Trier A.M. Li F. Kim S. Chen Z. 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