A basophil-neuronal axis promotes itch

Wang, Fang; Trier, Anna M.; Li, Fengxian; Kim, Seonyoung; Chen, Zhe; Chai, Jiani N.; Mack, Madison R.; Morrison, Stephanie A.; Hamilton, Jennifer D.; Baek, Jin Ok; Yang, Ting; Heul, Aaron M. Ver; Xu, An; Xie, Zili; Dong, Xintong; Kubo, Masato; Hu, Hongzhen; Hsieh, Chyi Song; Dong, Xinzhong; Liu, Qin; Margolis, David J.; Ardeleanu, Marius; Miller, Mark J.; Kim, Brian

doi:10.1016/j.cell.2020.12.033

Cited by 134 publications

(82 citation statements)

References 125 publications

(151 reference statements)

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“…Chronic itch is a hallmark feature of AD, mediated by the crosstalk between non-histaminergic sensory fibers, keratinocytes and immune cells (4). A recent study has demonstrated that while mast cells are required for acute allergic itch, a unique subset of IgE receptor+ basophils localize near free nerve endings and drive allergen-evoked itch flare ups in AD (92). During such a flare, degranulation of basophils releases leukotriene C4 causing activation of sensory neurons via its receptor CysLTR2, initiating itch signalling (92,93).…”

Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 99%

“…A recent study has demonstrated that while mast cells are required for acute allergic itch, a unique subset of IgE receptor+ basophils localize near free nerve endings and drive allergen-evoked itch flare ups in AD (92). During such a flare, degranulation of basophils releases leukotriene C4 causing activation of sensory neurons via its receptor CysLTR2, initiating itch signalling (92,93). Intraepidermal nerve fiber (IENF) density is higher in the skin of human AD patients compared to healthy controls (94).…”

Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 99%

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Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

2021

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Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.

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Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 99%

Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 99%

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

2021

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“…These results indicate that basophils were partly responsible for the Th2 immunity. Since basophils can account for inducing pruritis in AD [ 27 ], the alternative depletion of basophils showed a significant decrease in the scratching behavior and basophil population, but not mast cells, compared to the control mice ( Figure 3 b–d). This indicated that basophils played a role in the pathogenesis of AD, especially in triggering itchiness.…”

Section: Discussionmentioning

confidence: 99%

IL-37 Targets TSLP-Primed Basophils to Alleviate Atopic Dermatitis

Hou

Tsang

Kan

et al. 2021

IJMS

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Atopic dermatitis (AD) represents a severe global burden on physical, physiological and mental health. Innate immune cell basophils are essential for provoking allergic inflammation in AD. However, the roles of novel immunoregulatory cytokine IL-37 in basophils remain elusive. We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37. In the in vitro model, IL-37b significantly decreased Der p1-induced thymic stromal lymphopoietin (TSLP) overexpression in HaCaT cells and decreased the expression of TSLP receptor as well as basophil activation marker CD203c on basophils. IL-37 could also reduce Th2 cytokine IL-4 release from TSLP-primed basophils ex vivo. In the in vivo model, alternative depletion of basophils ameliorated AD symptoms and significantly lowered the Th2 cell and eosinophil populations in the ear and spleen of the mice. Blocking TSLP alleviated the AD-like symptoms and reduced the infiltration of basophils in the spleen. In CRISPR/Cas9 human IL-37b knock-in mice or mice with direct treatment by human IL-37b antibody, AD symptoms including ear swelling and itching were significantly alleviated upon MC903 challenge. Notably, IL-37b presence significantly reduced the basophil infiltration in ear lesions. In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.

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“…These T cells were increased in peripheral blood in patients with acute AD. In addition to the activated Th2 cells, increased ILC2s, basophils, eosinophils, and mast cells are also dominant sources during the acute stage of AD (58)(59)(60)(61)(62). These cells secrete large amount of Th2 cytokines, including IL-4, IL-5, IL-13, and IL-31.…”

Section: Ad-related Cytokines In Modulation Of Trp Channelsmentioning

confidence: 99%

Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis

Meng

Fischer

et al. 2021

Front. Immunol.

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Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

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A basophil-neuronal axis promotes itch

Cited by 134 publications

References 125 publications

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

IL-37 Targets TSLP-Primed Basophils to Alleviate Atopic Dermatitis

Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis

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