Complete overlap of interleukin-31 receptor A and oncostatin M receptor β in the adult dorsal root ganglia with distinct developmental expression patterns

doi:10.1016/j.neuroscience.2006.07.009

Neuroscience

Volume 142, Issue 4, 3 November 2006, Pages 1263-1271

https://doi.org/10.1016/j.neuroscience.2006.07.009 Get rights and content

Abstract

Interleukin-31 receptor A (IL-31RA) is a newly identified type I cytokine receptor, that is related to gp130, the common receptor of the interleukin (IL) -6 family cytokines. Recent studies have shown that IL-31RA forms a functional receptor complex for IL-31 together with the β subunit of oncostatin M receptor (OSMRβ). However, little is known about the target cells of IL-31 because it remains unclear which types of cells express IL-31RA. In our previous reports, we demonstrated that OSMRβ is expressed in a subset of small-sized nociceptive neurons of adult dorsal root ganglia (DRGs). In the present study, we investigated the IL-31RA expression in the adult and developing DRGs. From a northern blot analysis and in situ hybridization histochemistry, IL-31RA mRNA was found to be expressed in the adult DRGs. According to reverse-transcriptase polymerase chain reaction, IL-31RA mRNA was detected in the DRGs and trigeminal ganglia, while no expression of IL-31RA mRNA was observed in the CNS. Double immunofluorescence staining revealed IL-31RA to be expressed in a subset of small-sized neurons, all of which colocalized with OSMRβ. In addition, the expression of IL-31 RA was detected in afferent fibers in the spinal cord and the dermis of the skin. We also found that the developmental expression pattern of IL-31RA was different from that of OSMRβ; IL31RA-positive neurons in DRGs first appeared at postnatal day (PN) 10 and reached the adult level at PN14, whereas OSMRβ-positive neurons were observed at PN0 for the first time.

We previously demonstrated OSMRβ-expressing neurons to decrease, however, they were not found to disappear in oncostatin M (OSM) -deficient mice. These findings suggest that IL-31 and OSM may thus have redundant functions in the development of OSMRβ-expressing neurons.

Section snippets

Mice

In the present study, postnatal (0-, 7-, 10-, 12-, and 14-day-old) and adult (6- to 10-week-old) C57BL/6J male mice (Clea Japan, Tokyo, Japan) were used. These mice were kept under a 12-h light/dark cycle with food and water. At all times, the experiments were carried out under the control of the Animal Research Control Committee in accordance with the Guidelines for Animal experiments of Wakayama Medical University, Japanese Government Notification on Feeding and Safekeeping of Animals (No.

Expression of IL-31RA mRNA in CNS and peripheral nervous tissue specimens

We first examined the expression of IL-31RA mRNA in various regions of the CNS, TGs, and DRGs using a northern blot analysis. As shown in Fig. 1A, a single band of 4.8 kb corresponding to IL-31RA mRNA was strongly expressed in DRGs, while IL-31RA mRNA was not detected in TGs and other brain regions, including the cortex, cerebellum, olfactory bulb, hypothalamus, hippocampus and spinal cord. In addition, an RT-PCR analysis revealed that a single band corresponding to IL-31RA mRNA was detected in

Discussion

In the present study, we found that IL-31RA mRNA was highly expressed in the adult DRGs by both northern blot and RT-PCR analyses (Fig. 1, Fig. 5A). In situ hybridization histochemistry revealed that IL-31RA mRNA was expressed in a subset of small-sized DRG neurons. In addition, all the IL-31RA-expressing neurons contained OSMRβ in adult DRGs. These results suggest that a functional receptor for IL-31 exists in a subset of small-sized DRG neurons, which are TRPV1/P2X3/OSMRβ-triple positive (

Acknowledgments

This work was supported by a Research Grant on Priority Areas from Wakayama Medical University.

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Interleukin 31 (IL-31) is a neurocytokine that stimulates sensory neurons involved in pruritus. It contributes to skin barrier inflammation, dysfunction, and remodeling. As the immune and nervous systems are interrelated, IL-31 has a key role in the treatment of atopic dermatitis (AD) and prurigo nodularis (PN). Nemolizumab is a humanized monoclonal antibody that blocks the α subunit of the IL-31 receptor, modulates the neuroimmune response, and rapidly alleviates itching by directly blocking signaling. It reduces inflammation and lesion severity in AD and PN by restoring epithelial function and promoting skin barrier integrity. This review synthesizes the latest information on the functions of IL-31 and presents the current evidence, including clinical trial results, on the use of nemolizumab in the treatment of AD and PN.
La citoquina IL-31 es una neurocitoquina que estimula las neuronas sensoriales relacionadas con el picor, contribuye a la inflamación, la disfunción y remodelación de la barrera epidérmica. Al interrelacionar los sistemas inmunológico y nervioso constituye un factor clave en el tratamiento de dermatitis atópica (DA) y del prurigo nodular (PN). Nemolizumab es un anticuerpo monoclonal humanizado que bloquea la subunidad α del receptor de la IL-31 y modula la respuesta neuroinmunitaria, bloquea directamente la señalización del prurito y alivia rápidamente el prurito, controlando la inflamación y reduciendo la gravedad del eccema en DA y las lesiones pruriginosas del PN al restaurar la función epitelial y promover la integridad de la barrera cutánea.
Este artículo resume la nueva información relacionada con las funciones de la IL-31 y presenta la evidencia y resultados disponibles hasta el momento de los ensayos clínicos de nemolizumab en DA y PN.
Capsaicin suppresses interleukin-31-induced itching partially involved in inhibiting the expression of dorsal root ganglion interleukin-31 receptor A in male mice
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Citation Excerpt :
However, these effects may be unrelated to the suppression of itching considering that there are no reports that analgesic action inhibits itching more than 72 h following capsaicin application. It is reported that IL-31RA develops on C-fibers (Bando et al., 2006), and there may be TRPV1 and some kind of interaction to expression on the same C-fiber. We had previously reported that IL-31-induced itching partially participates in the analgesic effect of morphine in the periphery during the pain restraint mechanism (Tsuji et al., 2019).
To elucidate the mechanisms underlying the antipruritic effect of capsaicin, we investigated how topical application of capsaicin (0.01, 0.1 and 1.0% w/v) affects spontaneous scratching in NC/Nga mice, inerleukin-31 (IL-31) induced in BALB/c mice, and IL-31 receptor A (IL-31RA) and transient receptor potential vanilloid member 1 (TRPV1) mRNA expression in dorsal root ganglia (DRG). Capsaicin concentration-dependently suppressed long-lasting scratching (over 1.0 s, itch-associated scratching) and short-lasting scratching (0.3–1.0 s, locomotor activity) immediately after the application. Total long-lasting scratching and short-lasting scratching counts for 24 h and IL-31RA mRNA expression in the DRG significantly decreased with increasing concentration of capsaicin. Furthermore, 1.0% capsaicin suppressed long-lasting scratching and short-lasting scratching for more than 72 h. At this point, DRG IL-31RAmRNA was significantly decreased, but there was no change in cutaneous IL-31RA and TRPV1 mRNA. Thus capsaicin suppresses long-lasting scratching by inhibiting IL-31RA mRNA expression in the DRG. Next, we examined the effect of capsaicin on IL-31-induced long-lasting scratching in BALB/c mice. Repeated administration of IL-31 (50 μg/kg, subcutaneous) every 12 h for 3 days apparently increased long-lasting scratching counts and IL-31RA mRNA in the DRG. These increases were significantly suppressed by pretreatment with 1.0% capsaicin. TRPV1 mRNA in the DRG was also decreased within 1–24 h after capsaicin application. These results suggest that the strong and prolonged antipruritic action for IL-31-induced itching of capsaicin was caused by desensitization of C-fibers, and, in addition, the long-lasting inhibition of IL-31RA mRNA expression in the DRG.
New mechanism underlying IL-31–induced atopic dermatitis
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T_H2 cell–released IL-31 is a critical mediator in patients with atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuroimmune axis of the skin is unknown.
We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31–induced itch and neuroepidermal communication in patients with AD.
Ca²⁺ imaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31–stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects.
In human DRGs we confirmed expression and co-occurrence of oncostatin M receptor β subunit and IL-31 receptor A in a small subset of the neuronal population. Furthermore, IL-31 activated approximately 50% of endothelin-1–responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced soluble N-ethylmaleimide–sensitive factor activating protein receptor–dependent BNP release. In Grhl3PAR2^/+ mice house dust mite–induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31 transgenic mice also exhibited increased Nppb transcripts in DRGs and the skin; accordingly, skin BNP receptor levels were increased. Importantly, expression of BNP and its receptor were increased in the skin of patients with AD. In human skin cells BNP stimulated a proinflammatory and itch-promoting phenotype.
For the first time, our findings show that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and the skin. IL-31 enhances BNP release and synthesis and orchestrates cytokine and chemokine release from skin cells, thereby coordinating the signaling pathways involved in itch. Inhibiting peripheral BNP function might be a novel therapeutic strategy for AD and pruritic conditions.
IL-31: A new key player in dermatology and beyond
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Citation Excerpt :
Tissue distribution analysis of IL-31R revealed that IL-31RA is most abundantly expressed in dorsal root ganglia, where cell bodies of cutaneous sensory neurons are located.1 OSMRβ expression was demonstrated in a subset of small-sized nociceptive neurons in the dorsal root ganglia, all of which also colocalized with IL-31RA, which project to the inner portion of lamina II in the dorsal horn of the spinal cord and the dermis of the skin.15,31 Not only cutaneous but also intrathecal injections of IL-31 evoked intense itch and induced atopic-like dermatitis in murine skin.3
IL-31 is a novel cytokine expressed in many human tissues and involved mainly in T_H2-weighted inflammation. IL-31 signals through a receptor complex consisting of IL-31 receptor α and oncostatin M receptor β. The available data show that IL-31 is strongly linked with chronic pruritic skin disorders, such as atopic eczema, and represents a novel target for directed drug therapy. Regulation of immune responses and cellular differentiation and proliferation are recently elucidated effects of IL-31, suggesting a more complex and diverse area of effect for this novel cytokine. This review summarizes the current knowledge on IL-31 and its receptors and the involvement of IL-31 in diseases both in human subjects and mouse models.
Eosinophil-Related Disease and the Skin
2018, Journal of Allergy and Clinical Immunology: In Practice
Eosinophils are bone marrow-derived cells that infiltrate skin and mucous membrane in a broad spectrum of primary and reactive inflammatory diseases and malignancies. The eosinophil has potent proinflammatory activities, particularly, through the effects of its toxic granule proteins. In addition, eosinophils have prothrombotic and profibrotic activities. Eosinophil participation in the pathogenesis of certain diseases without identifiable intact eosinophil infiltration may not be recognized because eosinophil degranulation is poorly visualized on hematoxylin-and-eosin–stained histopathology sections. Eosinophil-related pathophysiology can involve virtually every component of skin. Commonly recognized dermatoses associated with eosinophils are arthropod bite and sting reactions and drug eruptions, “bugs and drugs.” Skin involvement is common in eosinophil-related systemic diseases including the hypereosinophilic syndromes. Eosinophil-related pathophysiology may play a key role in numerous disorders that, therefore, may benefit from therapies targeted to reduce or eliminate eosinophils.
Blockade of OSMRβ signaling ameliorates skin lesions in a mouse model of human atopic dermatitis
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Sensory systemComplete overlap of interleukin-31 receptor A and oncostatin M receptor β in the adult dorsal root ganglia with distinct developmental expression patterns

Abstract

Section snippets

Mice

Expression of IL-31RA mRNA in CNS and peripheral nervous tissue specimens

Discussion

Acknowledgments

Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory

Mol Cell Biol

IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis

J Allergy Clin Immunol

The capsaisin receptor: a heat-activated ion channel in the pain pathway

Nature

A P2X purinoceptor expressed by a subset of sensory neurons

Nature

Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice

Nat Immunol

GPL, a novel cytokine receptor related to GP130 and leukemia inhibitory factor receptor

J Biol Chem

Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling

Eur Cytokine Netw

Characterization of the signaling capacities of the novel gp130-like cytokine receptor

J Biol Chem

A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5

J Biol Chem

Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice

Blood

Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer

EMBO J

Gene expression of histamine H1 receptor in guinea pig primary sensory neurons: a relationship between H1 receptor mRNA-expressing neurons and peptidergic neurons

Mol Brain Res

Sensory system
Complete overlap of interleukin-31 receptor A and oncostatin M receptor β in the adult dorsal root ganglia with distinct developmental expression patterns