Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine

Chen, Yong; Wang, Zilong; Yeo, Michele; Zhang, Qiaojuan; López-Romero, Ana E.; Ding, Huiping; Zhang, Xin; Zeng, Qian; Morales‐Lázaro, Sara L.; Moore, Carlene; Jin, Yingai J.; Yang, Huanghe; Morstein, Johannes; Bortsov, Andrey V.; Krawczyk, Marcin; Lammert, Frank; Abdelmalek, Manal F.; Diehl, Anna Mae; Milkiewicz, Piotr; Kremer, Andreas E.; Zhang, Jennifer; Nackley, Andrea G.; Reeves, Tony E.; Ko, Mei‐Chuan; Ji, Ru-Rong; Rosenbaum, Tamara; Liedtke, Wolfgang

doi:10.1053/j.gastro.2021.03.049

Cited by 58 publications

(65 citation statements)

References 62 publications

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“…Mice with conditional deletion for Trpv4 in primary sensory neurons were generated by mating Trpv4 fl/fl with Nav1.8-Cre mice, as described previously (4). Efficiency of targeting Trpv4 was verified in both DRGs and TGs at gene and protein levels, see supplement data in study (4). All animal protocols were approved by the Duke University Institutional Animal Care and Use Committee (IACUC).…”

Section: Methodsmentioning

confidence: 99%

“…An allergic contact dermatitis model was established by applying 1-fluoro-2, 4-dinitrobenzene (DNFB) onto the neck-back skin as previously described (11). Scratch bouts were analyzed as previously described (4) in a blinded way.…”

Section: Methodsmentioning

confidence: 99%

“…Relative to the extensive studies on TRPV1 and TRPA in itch, TRPV4 has received little research attention until recently. TRPV4, a multimodally activated nonselective cation channel, has been detected in sensory neurons of dorsal root and trigeminal ganglion (DRG, TG) and skin cells (4–6), which are involved in itch sensation and development. Using Trpv4 knockout (KO) mice, several groups reported that it is required for pruritogens-evoked acute itch (7–9).…”

Section: Introductionmentioning

confidence: 99%

“…To determine cellular sites of action of Trpv4 in itch, we employed keratinocyte-Trpv4 conditional KO (cKO) mice and found that deletion of Trpv4 significantly reduced histaminergic (histamine and 48/80), but not non-histaminergic (chloroquine, CQ) pruritogens, -evoked acute itch (8). Additionally, we and others have recently revealed that TRPV4 in skin keratinocytes and macrophages also critically mediates chronic itch (4,5). Although these studies strongly suggest that TRPV4 in skin cells is essential for itch, whether neuronal-TRPV4 directly contributes to acute and chronic itch behaviors remains largely elusive.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of sensory neuron-TRPV4 in acute and chronic itch behaviors

Fang

Wang

Suttle

et al. 2021

Preprint

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Itch, particularly chronic itch, negatively impacts patients' physical, social, and psychological well-being, leading to deterioration in their quality of life. Limited understanding of itch mechanisms hinders the development of effective antipruritic treatments.TRPV4, a multimodally activated nonselective cation channel, has been detected in sensory neurons of dorsal root and trigeminal ganglion (DRG, TG) and skin cells (e.g. keratinocytes, mast cells, and macrophages). Recent evidence from experimental and clinical relevant studies has implicated that TRPV4 in skin cells plays an important role in both acute and chronic itch. In contrast, little is known whether TRPV4 in sensory neurons directly contributes to scratching behaviors. Here we used sensory neuron-Trpv4 conditional knockout (cKO) mice to address this question. Our results showed that TRPV4 in sensory neurons contributes to scratching behavior evoked by histaminergic (histamine and 48/80) and partial histaminergic (5-HT), but not non-histaminergic (SLIGRL and CQ) pruritogens. Moreover, we observed that TRPV4 in sensory neurons is required for dry skin, but not allergic contact dermatitis, -associated chronic itch. These findings suggest that neuronal-TRPV4 might be specific for some forms of acute and chronic itch.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of sensory neuron-TRPV4 in acute and chronic itch behaviors

Fang

Wang

Suttle

et al. 2021

Preprint

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“…5-hydroxytryptamine (5-HT) is an inflammatory and capable to induce itch in mice (not human), which is linked to TRPV4 function in epithelial and immune cells in skin, thus can be attenuated by TRPV4 antagonist HC067047 (173). Lysophosphatidylcholine (LPC)-induced scratching in mice was reduced by systemically TRPV4 inhibitors, GSK205 and HC067047, and the elevated LPC was previously observed in patients with AD (176).…”

Section: Mechanism Of Trp Family Antagonists As Therapeutics For Ad Treatmentmentioning

confidence: 95%

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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TRPV4: A trigger of pathological RhoA activation in neurological disease

2022

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Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface-localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton.Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4-RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood-brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4-RhoA activation in a range of neurological diseases.

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Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine

Cited by 58 publications

References 62 publications

Involvement of sensory neuron-TRPV4 in acute and chronic itch behaviors

Involvement of sensory neuron-TRPV4 in acute and chronic itch behaviors

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

TRPV4: A trigger of pathological RhoA activation in neurological disease

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