A specialized population of hair afferents dedicated to transmitting mechanical itch

Neuron  2026 Jun 4:S0896-6273(26)00409-5. doi: 10.1016/j.neuron.2026.05.017.

Mahar Fatima,1,9 Hankyu Lee,1,9 Hwayeon Cha,1,9 Chia Chun Hor,1 Feng Wang,2 Jingyi Liu,1 Jonathan Damblon,2 Wenwen Zhang,3 Katie Qu,1 Yumena Nagai,1 Abbey Dinh,1 Ziyan Wu,1 Ranveer Ajimal,1 Ailin Emily Xiong,1 Madeleine Chai,1 Alyssa Asmar,1 Wei Cai,3,6 Xiaowei Zhou,1 Anuraag Balaji,4 Haili Pan,1,7 Lorraine Horwitz,1 Lam C. Tsoi,4 Hongzhen Hu,5 X. Z. Shawn Xu,3,8 Yves De Koninck,2 and Bo Duan1,10,

*Correspondence: bduan@umich.edu

SUMMARY
Hairs serve as sensory structures that are crucial for perceiving environmental cues through interactions with
sensory endings. Depigmented and demedullated atypical hairs exhibit a limited distribution on mammalian
skin and have not been extensively studied. In this study, we identify a specific type of hair, termed vellus-like
hairs (VLHs), which are enriched in the postauricular region and on the hindpaws of mice. These hairs are
innervated by Aβ low-threshold mechanoreceptors (LTMRs) that co-express Toll-like receptor 5 and Calbindin1
(TLR5Calb1). Genetic ablation or silencing of these hair afferents eliminated mechanical itch generated by
gentle VLH stroking or indentation under both physiological and pathological conditions. Conversely, optogenetic
activation of TLR5Calb1 hair afferents evoked itch behaviors. Mechanosensitive Piezo2 channels in
TLR5Calb1 Aβ-LTMRs function as key mechanotransducers for mechanical itch signaling. Our study sheds
light on the previously poorly understood somatosensory physiology of unique hairs, emphasizing the significant
role of TLR5Calb1 Aβ-LTMRs in itch transmission.

https://doi.org/10.1016/j.neuron.2026.05.017

2026.07.03

Abstract

Chronic itch, particularly in cholestatic and uremic conditions, poses
a notable clinical burden, yet treatment options remain inadequate.
MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor
predominantly expressed in human sensory neurons, has emerged
as a critical mediator of cholestatic pruritus. Here we identified and
characterized HEP-50768, a potent and selective small-molecule inverse
agonist of hX4 through high-throughput screening and structure–activity
optimization. Structural elucidation through cryo-electron microscopy of
the hX4–inverse agonist complex structure revealed the unique binding
mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats,
HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors.
Comprehensive preclinical absorption, distribution, metabolism, excretion
and safety profiling was performed in both rats and monkeys, and these
findings establish HEP-50768 as a promising therapeutic candidate for
chronic itch, supporting its advancement to clinical evaluation.

Itch receptor MRGPRX4 interacts with the receptoractivity–modifying proteins

Ilana B. Kotliar1,2,‡ , Emilie Ceraudo1,‡ , Kevin Kemelmakher-Liben1 , Deena A. Oren3 , Emily Lorenzen1 ,
Tea Dodig-Crnkovic4 , Mizuho Horioka-Duplix1 , Thomas Huber1 , Jochen M. Schwenk4 , and
Thomas P. Sakmar1,5,*

Cholestatic itch is a severe and debilitating symptom in liver
diseases with limited treatment options. The class A G proteincoupled
receptor (GPCR) Mas-related GPCR subtype X4
(MRGPRX4) has been identified as a receptor for bile acids,
which are potential cholestatic pruritogens. An increasing
number of GPCRs have been shown to interact with receptor
activity–modifying proteins (RAMPs), which can modulate
different aspects of GPCR biology. Using a combination of
multiplexed immunoassay and proximity ligation assay, we
show that MRGPRX4 interacts with RAMPs. The interaction of
MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation
of basal and agonist-dependent signaling, which correlates
with a decrease of MRGPRX4 cell surface expression as
measured using a quantitative NanoBRET pulse-chase assay.
Finally, we use AlphaFold Multimer to predict the structure of
the MRGPRX4–RAMP2 complex. The discovery that RAMP2
regulates MRGPRX4 may have direct implications for future
drug development for cholestatic itch.

Psychological stress delays inflammatory resolution and promotes sustained sensory sensitization during recovery from atopic dermatitis

Qiaofeng Zhao, Alberto Leguina-Ruzzi, Mitsutoshi Tominaga, Yayoi Kamata, Atsuko Kamo, Huiying Wan, Yuping Ran, Kenji Takamori

Atopic dermatitis (AD) is a chronic inflammatory disorder characterized by pruritus, eczematous
lesions, and epidermal barrier dysfunction, with substantial impact on quality of life (Weidinger
and Novak 2016). Its pathogenesis reflects a complex interplay between barrier impairment,
immune dysregulation, and environmental triggers, resulting in heterogeneous phenotypes (Kim,
Kim et al. 2019). While mechanisms driving onset and exacerbation have been extensively studied,
the processes governing disease resolution remain poorly understood. Inflammatory resolution is
increasingly recognized as an active process involving immune reprogramming, tissue repair, and
restoration of homeostasis rather than a passive decline in inflammation (Oetjen, Mack et al. 2017).
Disruption of this process may contribute to persistent symptoms and chronic disease activity.
However, the factors that impair inflammatory resolution in AD remain poorly understood.
Psychological stress is a recognized modifier of AD, associated with worsened pruritus and disease
persistence. Experimental incorporation of stress paradigms has improved the translational
relevance of AD models (Hall, Cruser et al. 2012). Restraint stress (RS), a model of psychological
stress in rodents, activates the hypothalamic-pituitary-adrenal (HPA) axis and may enhance DRG
neuronal excitability through glucocorticoid and sympathetic signaling, thereby facilitating Aβ
fiber–mediated mechanical alloknesis (Buynitsky and Mostofsky 2009). However, prior work has
focused largely on stress during active inflammation, emphasizing exacerbation rather than
recovery. We hypothesized that psychological stress disrupts the transition to resolution without
amplifying peak inflammation, thereby sustaining sensory sensitization during recovery.

Epidermal PAR2-TRPV3-IL-33 Signaling Promotes Mast Cell Recruitment and Sensory Nerve-Mast Cell Interactions in Atopic Dermatitis

Jiahui Zhao 1,2 | Lingxuan Zhou 1 | Chenyu Wang 2,3,4 | Ziyan Rao 5,6 | Xiaohui Yuan 1 | Jun Cui 7 | Dongyu Zhao 5,6 | Ying Sun 8 | Yan Chen 8 | Ruoyu Li 1 | Miao Jing 2,3,4

1 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research
Center for Skin and Immune Disease, NMPA Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China | 2 Chinese Institute for
Brain Research, Beijing, China | 3 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,
China | 4 Basic Medical Sciences, Capital Medical University, Beijing, China | 5 Department of Biomedical Informatics, School of Basic Medical Sciences,
Peking University, Beijing, China | 6 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China | 7 National
Institute of Biological Sciences, Beijing, China | 8Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China

Keywords: atopic dermatitis | dermatology | mast cells

In silico discovery of nanobody binders to a G protein coupled receptor using AlphaFold Multimer

Edward P. Harvey^1,* , Jeffrey S. Smith^{1,2, *}, Joseph D. Hurley^1,*, Alyana Granados³, Ernst W. Schmid¹, Jason G. Liang-Lin¹, Huyang Zhang¹, Emily M. Meara^1,2, Elizabeth K. Wren¹, Steffanie Paul^4,5, Matthew P. Ferguson¹, Victor G. Calvillo-Miranda¹, Miguel A. Alcantar^1,6, Debora S. Marks^4,5, Johannes C. Walter^1,7, Andrew C. Kruse^1,†, Katherine J. Susa^3,†

¹Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
²Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, 02115,USA.
³Department of Pharmaceutical Chemistry, University of California, San Francisco, CA94158, USA
⁴Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
⁵Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
⁶Department of Biomedical Engineering, University of California, Irvine, CA, 92697, USA
⁷Howard Hughes Medical Institute, Boston, MA, USA
^*These authors contributed equally.
^†Correspondence to: Andrew C. Kruse (Andrew_kruse@hms.harvard.edu) and Katherine J. Susa (Katherine.Susa@ucsf.edu)

• Received02 October 2025
• Accepted03 April 2026
• Published23 April 2026

https://doi.org/10.1038/s41467-026-72093-5

Neuropsin, TRPV4 and intracellular calcium mediate intrinsic photosensitivity in corneal epithelial cells

Luka Lapajne ¹, Monika Lakk ², Christopher N Rudzitis ³, Shruti Vemaraju ⁴, Richard A Lang ⁴, Marko Hawlina ⁵, David Križaj ⁶

• ¹Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, University Medical Center, Ljubljana, Slovenia.
• ²Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA.
• ³Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA; Interdepartmental Program in Neuroscience, University of Utah, USA.
• ⁴Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
• ⁵Department of Ophthalmology, University Medical Center, Ljubljana, Slovenia.
• ⁶Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA; Interdepartmental Program in Neuroscience, University of Utah, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Department of Neurobiology, University of Utah, Salt Lake City, UT, USA. Electronic address: david.krizaj@hsc.utah.edu.

Abstract

Purpose: To investigate intrinsic phototransduction in the corneal epithelium and its role in intracellular and inflammatory signaling.

Methods: Optical imaging in isolated corneal epithelial cells (CECs) and debrided epithelia was combined with molecular, biochemical, pharmacological assays and gene deletion studies to track UVB-induced calcium signaling and release of cytokines, chemokines and matrix remodeling enzymes. Results from wild type mouse CECs were compared to data obtained from Opn5^-/- and Trpv4^-/- cells.

Results: UVB stimuli and TRPV4 activity induced epithelial release of IL-1β, IL-17, matrix metalloproteinases MMP-3/MMP-9, and thymic stromal lymphopoietin (TSLP). UVB stimuli evoked [Ca²⁺]_i elevations in dissociated mouse CECs that were partially reduced by inhibition of TRPV4 channels, Trpv4 knockdown and replacement of control saline with Ca²⁺-free saline. UVB-induced Ca²⁺ responses were significantly suppressed by OPN5 deletion and by inhibition of phospholipase C signaling, and responses were abrogated in cells with depleted intracellular Ca²⁺ stores.

Conclusions: Mammalian CECs are intrinsically and constitutively photosensitive. UVB photons are transduced by neuropsin, phospholipase C and CICR signaling, with mouse but not human CE transduction exhibiting a UVB-sensitive TRPV4 component. TRPV4 activity and UVB transduction are linked to cell-autonomous release of proinflammatory, matrix remodeling and nociceptive interleukins and MMPS. TRPV4-induced cytokine release may contribute to the pain induced by mechanical injury of the cornea and CEC photosensing may alert and protect the visual system from ultraviolet B (UVB) radiation -induced snow blindness, injury, vision loss and cancer.

Keywords: Corneal epithelium; Neuropsin; Phototransduction; Snow blindness; TRPV4.

Journal Club (2026.05.08)

Abstract
The Mas-related G protein-coupled receptor (MRGPR) X2 is expressed on skin mast cells
and can be stimulated by an unusually broad spectrum of ligands, including specific drugs
and even endogenous peptides. MRGPRX2 activation can induce mast cell degranulation
and consequently mediator release, leading to inflammatory and hypersensitivity reactions.
In addition, MRGPRX2 mediates pain and itching sensations, leading to increased efforts
to identify MRGPRX2 inhibitors, including plant-derived compounds. Components within
oat extracts have been shown to mediate anti-inflammatory and itch-relieving properties,
but a possible inhibitory effect on MRGPRX2 activation has not yet been investigated. We
aimed to fill this gap and explored whether an oat kernel extract can modulate MRGPRX2
activation. For this purpose, we established a mast cell model with the human LAD2
cell line and used it to investigate the consequences of exposure to oat extract. While
we did not observe any influence on cell viability, we analyzed the impact of oat extract
on MRGPRX2-mediated mast cell activation and degranulation initiated by the three
confirmed MRGPRX2 ligands c48/80, substance P, and cortistatin 14. Exposure to oat
extract resulted in a significant reduction in mast cell degranulation for all three ligands, as
assessed by the release of β-hexosaminidase, tryptase, cell surface expression of CD63 and
CD107a, and phosphorylation of ERK. All results were confirmed with primary human
mast cells. Thus, we demonstrated for the first time that oat extract leads to a significant
reduction in MRGPRX2 activation, pointing to a previously unrecognized capacity of
natural compounds to modulate this pathway.
Keywords: mast cells; MRGPRX2; oat extract