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.

IL-33, and TSLP).An important property of these cytokines is their ability to activate or sensitize peripheral sensory neurons.For example, IL-4, IL-13, and IL-31 trigger rapid calcium responses in dorsal root ganglion (DRG) neurons and promote itch, 18,19,74 and IL-5 has been implicated in the release of vasoactive intestinal peptide (VIP) from sensory neurons in the lungs. 757][78][79][80] Neurons and immune cells colocalize in affected areas of the skin in AD and PN and in the airways in asthma. 7,8,53In addition, patients with AD and PN often show alterations in nerve fibers in affected tissue. 10,42,43,81IL-31, a type 2 cytokine associated with itch, has been shown to promote sensory nerve elongation, branching, and density both in vitro and in lesional skin in mice. 82In asthma, sensory neurons also exhibit hyperinnervation; for example, IL-5 exposure in utero enhances nerve sprouting in lungs in mice. 83e mechanisms by which sensory neurons, their associated neuropeptides, and tissueresident or infiltrated immune cells interact to activate or regulate specific pathways of inflammation, and how these histologic alterations affect the precise sensory response and neuroinflammatory function of organs across diseases featuring type 2 immune dysregulation (including AD, PN, asthma, CRSwNP, and EoE) remains a major area of inquiry.Herein, we review current research on these pathways and present recent advances in targeted treatments to reduce type 2 inflammation and associated sensory pathologies in these diseases.

NEUROIMMUNE CROSS TALK AND SENSORY PATHOLOGY IN CONDITIONS ASSOCIATED WITH TYPE 2 INFLAMMATION
The itch-scratch cycle in AD and PN AD and PN are chronic inflammatory skin disorders featuring intense pruritus and an itchscratch cycle. 84Both diseases are often accompanied by pruritic skin, sleep disturbances, and impaired quality of life. 44,85However, there are notable differences.AD is a relapsingremitting type 2 inflammatory disease characterized by red, scaly, oozing, and crusted lesions, as well as by increased risk for cutaneous infections and intermittent flares. 86- 90In contrast, PN is a chronic pruritic condition with type 2 immune dysregulation with or without atopy.In addition to intense pruritus lasting for 6 weeks or longer, PN features discrete papulonodular lesions with firm fibrotic qualities. 85,91,92Although AD is considered a primary inflammatory dermatosis that secondarily results in pruritus, PN may be initiated by sensory neuron dysfunction, resulting in itch that is triggered independently of a pruritogen stimulating the neuron that can cause secondary fibrotic papulonodular lesions as a result of mechanical disruption of the skin from vigorous scratching. 44e itch-scratch cycle refers to a vicious cycle in which pruritus drives repeated scratching, which in turn further exacerbates pruritus either directly by mechanical sensitization of nerves or indirectly via release of trauma-induced inflammatory mediators.In this cycle, abnormal neuroimmune cross talk promotes a positive feedback loop that drives sensitization to pruritogens and itch amplification (Fig 3). 11ltiple and overlapping mechanisms can lead to itch, which can be acute or chronic.Triggers include exogenous pruritogens, endogenous pruritogens produced by keratinocytes and immune cells, and mechanical stimuli (eg, from light touch). 93,94In a genomewide association study, exogenous itch from mosquito bites showed a strong association with cytokine pathway loci, including interferon regulatory factor 1 (IRF1), IL3, colonystimulating factor 2 (CSF2), and IL21, along with a weaker association with other loci, including IFN-γ-AS1 (IFNG-AS1) and signal transducer and activator of transcription (STAT) 6 (STAT6). 95In addition, acute itch is initiated primarily via histamine release from mast cells and basophils through degranulation following activation by allergens via IgE or via inflammatory mechanisms, as seen in acute urticaria and, less commonly, in chronic urticaria. 48Mechanical stimuli activate Piezo1 channels on itch sensory neurons.In mouse models, stimulation of Piezo1 evoked alloknesis (defined as an itch response evoked by light touching of skin, particularly in dry or aging skin). 94This suggests that itch-specific sensory neurons, which also express IL-4 receptor alpha (IL-4Rα), 18 could be pathologically stimulated via type 2 neurogenic inflammation, and itch could be further amplified by excessive touch or scratching via the Piezo1 transducer.98][99][100][101][102][103] The IL-4-and IL-13-mediated Janus kinase (JAK) and STAT intracellular signaling pathways are critical for T H 2 cell differentiation and type 2 inflammatory processes.Inhibition of JAK/STAT signaling can improve clinical symptoms of AD, including itch. 37,41,104Binding of IL-4 and IL-13 to IL-4Rα activates JAK1, JAK3, tyrosine kinase 2, and STAT6.[107] Chronic itch in AD and PN is induced largely via non-histaminergic mediators.Type 2 inflammatory cytokines activate nonhistaminergic itch in multiple ways. 11In response to pruritic stimuli, scratching-induced skin stress or damage (eg, resulting from dry skin) can cause keratinocytes to release alarmins, including TSLP and IL-33, which can trigger pruritus by acting directly on sensory neurons. 11,14-16IL-33 may also play an indirect role in severe itch by initiating the IL-33/ST2/CGRP axis, which has been shown to promote interactions between type 2 inflammatory cells and somatosensory neurons to induce itch in allergic conjunctivitis. 111Notably, a clinical trial of the anti-TSLP mAb tezepelumab in patients with moderate-to-severe AD found little to no efficacy in itch (versus that with placebo), suggesting that TSLP may have only a limited role in pruritus in AD. 17 Type 2 cytokines and related factors (such as OSM) may have a prominent role in chronic pruritus and sensitization to pruritogens.Both IL-4 and IL-31 are implicated in the transmission of the pruritic sensation in atopic diseases, with IL-4 promoting T H 2 cell polarization, thereby contributing to increased IL-31 expression levels observed in both AD and PN lesional skin. 9When compared with their expression in samples from nonatopic patients, expression of IL-4 and IL-13 (both of which bind to IL-4Rα) is increased in patients with AD lesions. 112A subset of neurons coexpress neuropeptides and receptors for type 2 cytokines, including IL-4Rα and IL-31 receptor A (IL-31RA) 18 ; for example, some sensory neurons in skin coexpress IL-31RA, TRPV1, and TRPA1 in the DRGs. 19These cation channels mediate the release of neuropeptides such as CGRP and SP and are essential for the itch-inducing effects of IL-31, thus providing a direct link between type 2 inflammatory cytokines and neurogenic inflammation. 19IL-4Rα stimulation activates sensory neurons and enhances their response to pruritogens (such as IL-31 and histamine) via transient receptor potential channels and JAK1 pathways. 11,18,84,97In human sensory neurons, exposure to type 2 cytokines (eg, IL-4, IL-13, IL-25, IL-31, IL-33, TSLP) increases sensory neuron excitability, amplifies the neuronal response to pruritogens, and alters activity of downstream gene transcription factors related to AD and itch (including TRPV1 and TPRA1). 18,113,114OSM, which shares a coreceptor with IL-31, also promotes sensitization of itch-specific neurons and is correlated with itch intensity. 49,9712]48 Mast cells are particularly well positioned to act as a link between the nervous and immune systems, as they are often found near afferent nerve fibers. 7,8Many neuropeptides have direct effects on mast cells, promoting mast cell degranulation and the production of type 2 cytokines and chemokines. 76][117][118] Basophils can also interact with sensory neurons, mediating allergeninduced itch in the context of AD-associated inflammation. 13Interestingly, basophils have been reported to express MRGPRX2, demonstrating the diversity of ways in which granulocytes engage in a bidirectional positive neuroimmune feedback loop that may facilitate and maintain states of pathologic sensation and chronic inflammation. 119][47] VIP concentrations are also higher in patients with AD than in individuals without AD. 120roteases derived from house dust mites are common allergens that trigger the release of SP from TRPV1-expressing sensory neurons, which activates mast cells via MrgprB2 in mice and recruits dendritic cells that prime type 2 differentiation. 61,80In addition, scratching may stimulate the release of neuropeptides, including CGRP, nerve growth factor, and VIP. 11,84aken together, these findings suggest that allergens and other environmental stimuli may directly stimulate both itch and neurogenic inflammation via neuropeptides such as SP.
The extracellular matrix protein periostin is overexpressed in the skin of patients with AD and may also contribute to itch.TSLP induces periostin secretion in keratinocytes, which promotes JAK/STAT signaling and T H 2 cell immunity; it also interacts with integrins to promote immune cell activity and directly stimulate nerve fibers.In PN, periostin expression was reported to be correlated with itch and was independent of IL-31 expression, indicating an independent pathway of PN-related itch. 121though scratching can temporarily relieve pruritus by activating fibers that block itch sensation in the spine, repeated scratching can cause mechanical disruption of the skin, leading to the aforementioned neural, immunologic, and epithelial changes that further exacerbate pruritus.In normal skin, scratching relieves itch by activating Piezo2 ion channels on Merkel cells, which simulate Ab fibers to reduce itch.In dry skin, the same signaling pathway can activate MRGPRA3-positive pruriceptors that exacerbate itch and drive the itch-scratch cycle. 122,123In addition to miswiring in the periphery, scratching also activates reward regions of the brain.Structural and functional changes have been observed in the brain's motor and reward regions in patients with chronic pruritus, suggesting that the itch-scratch cycle may be perpetuated at the level of the central nervous system. 124An active area of exploration is the inflammatory cross talk between the periphery and the brain and the way in which inflammatory circuits within peripheral tissue can imprint durable alterations within the nervous system to drive pathologic sensation and neuroinflammation.
The physiologic mechanisms of itch can change with age, which may explain differences in pruritus across a patient's lifetime.Merkel cells in the skin suppress mechanical itch in pruriceptive C neurons via cutaneous Piezo2 activation; these cells decrease in number with age. 122,123,125In addition, MRGPRA3-positive pruriceptors become more closely associated with Merkel cells in chronic itch models. 122,123An increase in alloknesis arising from a hypersensitive itch response, which is often seen in dry or aging skin, is correlated with the loss of Merkel cells with age. 122,123Similar observations in the oral mucosa may explain loss of ability to effectively chew and swallow with age. 1268][129][130] These findings may help explain the higher prevalence of PN in older adults and patients with other chronic pruritic conditions. 131,132o mAbs, dupilumab and tralokinumab, have been approved for the treatment of AD in several countries, [133][134][135] whereas a third mAb, nemolizumab, has been approved in Japan for treatment of itch associated with AD when other treatments are ineffective. 13638 Multiple randomized placebocontrolled clinical trials of dupilumab (with or without concomitant topical corticosteroids) in adults, adolescents, children, and infants with moderate-to-severe AD have demonstrated that dupilumab significantly improves clinical signs and neuroimmune inflammation-driven symptoms (including itch), as well as other patient-reported outcomes.[20][21][22][23][24][25][26]139 Tralokinumab and lebrikizumab both bind to IL-13 and have been shown to improve signs and symptoms of moderate-to-severe AD. [27][28][29][30][31][32][33] Nemolizumab, an anti-IL-31 receptor 1 mAb, has demonstrated activity in AD and PN.34,36,50,136 JAK inhibitors (JAKIs), such as abrocitinib, baricitinib, and upadacitinib, are also approved and have demonstrated efficacy in AD. [37][38][39][40][41]

Airway type 2 inflammation, hyperresponsiveness, and reduced expiratory volume in asthma
Asthma is a chronic respiratory disease characterized by airflow obstruction, increased mucus production, airway inflammation, and hyperresponsiveness.The pathophysiology of asthma is multifactorial, and multiple types of immune cells have been implicated in its development.1][142] These cytokines promote airway obstruction and tissue remodeling, including smooth muscle contraction, basement membrane thickening, eosinophilia, goblet cell hyperplasia, and mucus production. 2,140,142- 144IL-4 and IL-13 induce production of eotaxin, which cooperates with IL-5 in promoting eosinophilia in the respiratory epithelium. 2,140IL-5 is a potent regulator of eosinophil growth, differentiation, migration and survival, and it plays a key role in asthmaparticularly the eosinophilic phenotype. 1,142,145,146IL-31 may also contribute to the production of type 2 inflammatory factors and recruitment of immune cells in the lung. 147milar to the bidirectional neuroimmune cross talk observed with the itch-scratch cycle in AD and PN, reciprocal neuroimmune interactions may perpetuate airway inflammation and sensory pathologies in asthma (Fig 3). 148Sensory neurons of the vagal ganglia densely innervate the conducting airways of the lung; those of the nodose ganglia can extend into the alveolar region. 149,1509][150] Inhaled ovalbumin, a commonly used allergen in animal models of asthma, as well as type 2 inflammatory mediators such as IL-5, can directly activate calcium signaling in cultured nodose neurons. 75In vivo genetic ablation or chemical inactivation of voltage-gated sodium channel 1.8-expressing vagal nociceptor neurons has been shown to blunt allergen-induced increase in immune cells. 75However, in a separate study, in vivo genetic ablation of largely overlapping TRPV1-expressing vagal nociceptor neurons did not affect allergen-induced increases in immune cells. 151Thus, whether vagal sensory neurons are required for regulating allergen-induced T H 2 cell airway immune responses remains unclear.
Neuropeptide release from sensory neurons may have a role in asthma.Levels of SP are increased in induced sputum and correlated with airway obstruction, and CGRP level is elevated in bronchoalveolar lavage fluid. 152,153Neuropeptide release by sensory neurons positive for TRPA1 or TRPV1, which are markers of nociceptors, may play a particularly important role in this setting. 154,155For example, in cultured vagal ganglia nociceptive neurons, IL-5 stimulates the release of neuropeptides, such as VIP, that stimulate CD4positive T cells and ILC2s, which in turn release type 2 cytokines such as IL-5, thereby amplifying allergic inflammation.In contrast, silencing these neurons ameliorates airway inflammation. 75In addition, cholinergic neurons in the gut and lung release neuromedin U, which promotes ILC2 response. 59,60,1568][159] How sensory neurons and autonomic neurons interact to regulate inflammation remains poorly understood, despite the availability of many therapies targeting adrenergic and cholinergic pathways in the airway.For example, CGRP and neuromedin U have divergent effects, demonstrating the complexity of the mechanisms by which neuropeptides regulate type 2 inflammation. 160,161The central nervous system has been shown to exert systemic anti-inflammatory effects via the vagus nerve by inhibiting splenic macrophages in the cholinergic anti-inflammatory pathway, and some evidence suggests that manipulation of the vagus nerve (with cholinergic agonists or vagal nerve stimulation) may modulate lung inflammation. 162ronic respiratory inflammation can sensitize nerve fibers that innervate the airways, resulting in smooth muscle hypercontraction and airway constriction, ultimately resulting in airway hyperresponsiveness (AHR).AHR is correlated with the severity of asthma and is a cardinal feature associated with the degree of treatment necessary to control symptoms. 148n the human airway, mast cell numbers within the airway smooth muscle bundle are correlated with the severity of AHR. 57A murine model devoid of mast cells shows blunted AHR. 58Eosinophils also play a role in bronchoconstriction and are recruited by eotaxin to cluster at airway nerves; preclinical models suggest that IL-4 and IL-13 increase expression of eotaxin in parasympathetic neurons. 535][56] IL-13 has also been shown to upregulate periostin in airway epithelium. 163mpathetic and parasympathetic neurons (and their reciprocal interactions with sensory neurons and immune cells) contribute to the clinical manifestations of asthma. 46ympathetic neurons release the neurotransmitter noradrenaline, which induces airway smooth muscle relaxation via β2-adrenergic receptors (β2Ars) on smooth muscle cells. 46β2AR agonists, which are often used as bronchodilators for the treatment of asthma, may influence immune cells.For example, β2AR agonists reduce IL-33induced airway inflammation and suppress ILC2 proliferation. 46,62Immune cells also influence noradrenergic function: mast cell-derived transforming growth factor β triggers phosphorylation of β2AR on smooth muscle cells, which reduces the response to albuterol, a β2AR agonist. 164Finally, eosinophils increase sensory nerve responsiveness and density in the airway and release mediators that antagonize inhibitory M 2 muscarinic receptors on parasympathetic nerves.The effects of eosinophils on both sensory and parasympathetic nerves potentiate bronchoconstriction. 165 Rare sensory cell types in the lung epithelium also play important roles in sensing allergens and in asthma pathogenesis. 166,167Pulmonary neuroendocrine cells are activated by allergens to increase their production of neuropeptides, such as CGRP, and neurotransmitters, such as γ-aminobutyric acid.These cells are essential for amplifying allergen-induced responses, including activation of ILC2s, recruitment of T H 2 immune cells, and goblet cell metaplasia. 63Similarly, tuft cells can detect allergens and release neurotransmitters (such as acetylcholine), alarmins (such as IL-25), and inflammatory mediators (such as leukotrienes) that can contribute to allergic inflammation in the airways. 168,169Tuft cells also promote respiratory reflexes such as sneezing and coughing. 167,169x biologics have been approved for treatment of asthma: omalizumab, mepolizumab, reslizumab, benralizumab, tezepelumab, and dupilumab. 170,171Omalizumab is a humanized mAb directed against IgE. 170,171In multiple clinical trials, omalizumab significantly improved signs and symptoms of asthma; for example, it reduced exacerbation rates, improved lung function and symptoms of asthma, and reduced use of inhaled corticosteroids (vs oral corticosteroids). 171Mepolizumab, reslizumab, and benralizumab inhibit the IL-5 pathway (a key regulator of eosinophils) by targeting either IL-5 (mepolizumab and reslizumab) or the IL-5 receptor (benralizumab). 172All 3 were well tolerated and reduced asthma exacerbations in clinical trials in adults and adolescents with severe eosinophilic asthma that was otherwise inadequately controlled with standard therapies. 172Tezepelumab, which targets the epithelial cell-derived cytokine TSLP, reduced asthma exacerbation rates in a phase 3 trial, 173 and in a long-term, randomized, placebo-controlled extension study, it continued to reduce exacerbation rates for up to 104 weeks. 1746][177] Given the neuroimmune effects of eosinophils in asthma, it is possible that blockade of IL-4, IL-5, IL-13, and TSLP may alter these effects, thereby addressing some of the underlying pathophysiologic mechanisms of asthma.
These therapeutics reveal important differences in the tissue-specific effects of type 2 cytokines.Although anti-IL-5 therapies and tezepelumab have been successful and approved for use in asthma, they have not been successful in AD.Therapies specifically targeting IL-13 alone have advanced in AD but have failed in asthma.However, dual blockade of IL-4 and IL-13 has been successful in both diseases.Notably, although the IL-5 receptor has been reported in the nodose ganglia of the lung, 75 the DRGs for the skin lack this receptor. 18

Loss of smell in CRSwNP
CRSwNP is a chronic inflammatory disease of the nasal mucosa and paranasal sinuses.Clinical manifestations include nasal congestion, rhinorrhea/postnasal drip, facial pain or headache, and impaired sense of smell.Notably, pruritus often accompanies CRSwNP, and increased levels of periostin have been found in the nasal mucosa of patients with CRSwNP. 121Levels of IL-31 are also increased in patients with allergic rhinitis (AR); in this setting, IL-31 is induced by IL-4 and promotes type 2 inflammation. 50Olfactory dysfunction in CRSwNP is common and negatively affects quality of life. 178,179The mechanisms underlying olfactory dysfunction in CRSwNP are multifaceted, involving changes to the olfactory mucosa following (and related to) the type 2 inflammatory response, disruption of synaptic transmission resulting from neuroepithelial edema, and decreased airflow in the olfactory cleft (Fig 3). 180,181Nasal obstruction may contribute to olfactory dysfunction, but it is unlikely to be the primary driver because the sense of smell does not always return after polypectomy. 182,183However, the extent of inflammation in the neuroepithelium is correlated with the severity of olfactory dysfunction. 184SwNP has a prominent type 2 inflammatory signature. 1856][187] Release of inflammatory mediators triggers hypersecretion of olfactory mucus, resulting in changes in ion concentration that can affect the activity of olfactory neurons. 187In a mouse model of chronic rhinosinusitis, chronic type 2 inflammation reduced the number of immature neurons, suggesting that chronic inflammation may inhibit olfactory sensory neurogenesis, rendering the olfactory mucosa less able to recover from injury. 65In another mouse study, IL-4Rα was expressed in olfactory sensory neurons; however, although both IL-4 and IL-13 increased calcium uptake (indicating activation) in these neurons, mice developed anosmia following intranasal administration of IL-4, but not IL-13. 64ansient receptor potential channels such as TRPA1, TRPV1, transient receptor potential vanilloid 4 (TRPV4), transient receptor potential cation channel subfamily M member 4 (TRPM4), and transient receptor potential cation channel subfamily M member 8 (TRPM8) are expressed in the upper airway in epithelial cells, sensory neurons, T cells, and mast cells. 66These channels respond to physical stimuli (eg, changes in temperature) and chemical stimuli, and they are associated with type 2 inflammatory processes in the upper airway. 66For example, desensitization or ablation of TRPV1-positive sensory fibers in mice reduced allergy-associated and chemically induced sneezing, which were mediated by neuropeptides such as neuromedin B. 67 In another mouse model of AR, knockout or inhibition of TRPV1 suppressed T H 2/T H 17 cytokine production, eosinophil infiltration, and IgE in nasal mucosa. 68Similarly, patients with AR had higher numbers of TRPV1-positive cells in the nasal mucosa than healthy controls did. 68cent studies suggest that biologics may improve the olfactory changes associated with CRSwNP.Currently, 3 biologics are approved for CRSwNP: omalizumab, mepolizumab, and dupilumab.Omalizumab improved clinical and endoscopic aspects of CRSwNP, including sense of smell. 188,189Mepolizumab improved nasal obstruction in a phase 3 trial, with modest improvement in sense of smell. 1902][193] IL-4Rα is present on olfactory sensory neurons 64 ; however, further research is needed to elucidate the relationship between this receptor and the neuroimmune mechanisms underlying such swift restoration of olfaction.

Dysphagia in EoE
EoE is a chronic inflammatory disease of the esophagus.Primary symptoms include dysphagia and food impaction in adults and failure to thrive, feeding difficulties, and vomiting in infants and children. 194,195These symptoms are consistent with dysregulated neural control of the esophagus and inflammation-driven tissue remodeling. 69,70,196EoE is characterized by a type 2 inflammatory response (Fig 3).Type 2 inflammation-derived nociceptor sensitization of the esophagus leads to pain, motor dysfunction and eventually tissue remodeling. 69,70Following exposure to food-related antigens, esophageal epithelia secrete TSLP and IL-33, causing T H 2 cells to release IL-4, IL-5, and IL-13.The presence of IL-4 and IL-13 induce dilated intracellular spaces and basal cell hyperplasia in the esophageal epithelia, whereas IL-5 and eotaxin-3 promote infiltration by eosinophils and possibly by mast cells and basophils. 70,195,197[200] Increased infiltration of eosinophils and mast cells in esophageal tissue may increase vagal sensory neuronal responsiveness to acid, promoting barrier dysfunction and impaired epithelial permeability. 71,72Increased epithelial permeability may enhance the ability of luminal acid to stimulate action potential discharge in nociceptive afferent terminals.Type 2 cytokines can also cause hypercontractility of gastrointestinal smooth muscle cells via signal transducer and activator of transcription 6 (STAT6) or mitogen-activated protein kinase (MAPK) signaling pathways, which may contribute to dysphagia. 71PV1 and mast cells may modulate pain in EoE.In a study in patients with EoE with pain, pain was positively associated with molecular expression of TRPV1, carboxypeptidase A3, and hematopoietic prostaglandin D synthase but not eosinophilia; mast cells colocalized with neurons, which is suggestive of mast cell specificity. 73Neuropeptides such as SP and VIP promote mast cell degranulation, the production of type 2 cytokines and chemokines, and a resultant immune cascade. 7Because TRPV1-positive sensory neurons are prominent within the vagus nerve and have itch-specific transcriptional identity at the single-cell level, 201 symptoms of discomfort and irritation associated with EoE may be defined by molecular and cellular circuits that resemble itch mechanisms rather than traditional painassociated pathways.
3][204] Similarly, lirentelimab, which targets sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8), reduced eosinophil counts but failed to improve symptoms in patients with EoE. 205Agents targeting IL-13 have produced positive results; they include the anti-IL-13 mAbs QAX576 and RPC4046 206,207 and dupilumab, which inhibits both IL-4 and IL-13 signaling. 208,209Dupilumab is the first US Food and Drug Administration-approved drug for the treatment of EoE.In clinical trials in patients with EoE, dupilumab reduced peak intraepithelial eosinophil counts in esophageal tissues and improved clinical, histologic, and endoscopic scores. 208,209us, the success of therapeutics targeting the type 2 inflammation spectrum is highly dependent on tissue-specific mechanisms.Future studies will be required to determine how epithelial, stromal, and neural pathways, influenced by type 2 cytokines, imprint unique responses within specific tissues.

DISCUSSION
Multiple links connect neuroimmune cross talk, inflammatory pathways, and sensory pathologies across type 2 inflammatory diseases.Type 2 inflammation promotes alterations in neural and immune effectors and their interactions, leading to both sensory and autonomic dysfunction in AD, PN, asthma, CRSwNP, and EoE.Reciprocal neuroimmune interactions may perpetuate inflammation and sensory pathology in these diseases.For example, in AD, strong evidence supports a role for type 2 inflammation in a positive feedback loop of sustained neural and immunologic changes that drive sensory and behavioral pathology (ie, the itch-scratch cycle), which may contribute to the chronic nature of AD.In contrast, PN exemplifies how a potentially neurogenic process can also be linked to type 2 inflammation and drive inflammatory and fibrotic pathology in the skin.Neuroimmune changes have been well characterized in AD and asthma, but such changes are less well characterized in PN, CRSwNP, and EoE.Interestingly, studies in multiple type 2 inflammatory diseases have demonstrated that mast cells colocalize with afferent nerve terminals in epithelial tissues and sensitize nociceptive C-fibers. 7,8,48,57,65,69,73,164,186As such, these cells may constitute a shared element in type 2 inflammatory diseases at different epithelial surfaces and neuroimmune manifestations.Further research is needed to better understand whether similar feedback loops also occur in other organs susceptible to type 2 inflammatory manifestations.

DISCLOSURE STATEMENT
Sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

AD
Atopic dermatitis Sensory pathologies in atopic diseases.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.