JID Innovations In Press, November 2024
Olive C. Osuoji MD, Taryn DeGrazia MD, Emily F. Cole MD MPH, Katy Lawson, Henry Hilley, Yanyan Xing, Liang Han, Sarah Chisolm MD, Xiobo Yan, Yuxian Sun, Yuan Liu, Suephy C. Chen MD, Ron J. Feldman MD
Bullous pemphigoid (BP) is a devastating autoimmune blistering disease with need for improved therapeutics. Limited data is available on the overall burden of pruritus and alterations over time, however treatment of itch specific pathways may provide novel therapeutics. In this paper, we analyzed the quality-of-life (QOL) impact particularly related to itch and determined corresponding changes in intraepidermal nerve fiber density (IENFD) and gene expression. 43 BP patients were followed prospectively on standard-of-care treatment and showed average BPDAI total activity score (TAS) decrease from 19.1 ± 19.2 to 8.2 ± 11.3 and improvement in QOL measures ABQoL, TABQoL and ItchyQoL. At baseline, IENFD in BP and Atopic Dermatitis (AD) patients were significantly lower than healthy controls (7.3 ± 1.5, 3.2 ± 2.0 and vs. 9.7 ± 5.4 fibers/mm, p=0.031) and increased from baseline to follow-up visit, (11.7 ± 0.4 and 5.8 ± 2.7) although only AD reached statistical significance (p=0.018). S100A8, S100A9, CCL17 and CCL18, genes were highly upregulated in the skin of BP patients compared to healthy controls. Our data provides evidence for improvements in itch-related QOL over time on standard of care therapies with unique alterations in inflammatory mediators related to early immune cell activation and recruitment.
American Journal of Respiratory Cell and Molecular Biology In Press, October 2024
Yanyan Xing , Yeseul Nho , Katy Lawson , Yuyan Zhu , Alexandra E Ellison , Margaret Y Chang , William Hancock , and Liang Han
The lung is densely innervated by sensory nerves, the majority of which are derived from the vagal sensory neurons. Vagal ganglia consist of two different ganglia, termed nodose and jugular ganglia, with distinct embryonic origins, innervation patterns, and physiological functions in the periphery. Since nodose neurons constitute the majority of the vagal ganglia, our understanding of the function of jugular nerves in the lung is very limited. This study aims to investigate the role of MrgprC11+ jugular sensory neurons in a mouse allergic asthma model. Our previous study has shown that MrgprC11+ jugular neurons mediate cholinergic bronchoconstriction. In this study, we found that in addition to MrgprC11, several other Mrgpr family members including MrgprA3, MrgprB4, and MrgprD are also specifically expressed in the jugular sensory neurons. MrgprC11+ jugular neurons exhibit dense innervation in the respiratory tract including the larynx, trachea, proximal, and distal bronchus. We also found that receptors for IL-4 and oncostatin M, two critical cytokines promoting allergic airway inflammation, are mainly expressed in jugular sensory neurons. Both IL-4 and oncostatin M can sensitize the neuronal responses of MrgprC11+ jugular neurons. Moreover, ablation of MrgprC11+ neurons significantly inhibited airway hyperresponsiveness in the asthmatic lung, demonstrating the critical role of MrgprC11+ neurons in controlling airway constriction. Our results emphasize the critical role of jugular sensory neurons in respiratory diseases.
Cell In Press, July 2024
Haowu Jiang, Huan Cui, Mengyu Chen, Fengxian Li, Xiaolei Shen, Changxiong J. Guo, George E. Hoekel, Yuyan Zhu, Liang Han, Kangyun Wu, Michael J. Holtzman, and Qin Liu
Sneezing and coughing are primary symptoms of many respiratory viral infections and allergies. It is generally assumed that sneezing and coughing involve common sensory receptors and molecular neurotransmission mechanism. Here we show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11+MrgprA3-) mediates sneezing responses to a multitude of nasal irritants, allergens and viruses. Although this population also innervates the trachea, it does not mediate coughing as revealed by our newly established cough model. Instead, a distinct sensory population (SST+) mediates coughing but not sneezing, unraveling an unforeseen sensory difference between sneezing and coughing. At the circuit level, sneeze and cough signals are transmitted and modulated by divergent neuropathways. Together, our study reveals the first difference in sensory receptors and neurotransmission / modulation mechanisms between sneezing and coughing, offering neuronal drug targets for symptom management in respiratory viral infections and allergies.
Journal of Investigative Dermatology In Press, May 2024
Yanyan Xing, Yeseul Nho, Katy Lawson, Haley Steele, and Liang Han
Our results demonstrate regional differences in itch processing, with higher itch sensitivity in glabrous skin, aligning with the regionally distinct morphological organization of itch-sensing neurons. MrgprC11+ neurons exhibit low IEND and larger axonal arborization in glabrous skin, and regionally distinct central arbors in the spinal cord. Previous studies have linked regional-specific central arbor morphology to enhanced signal transmission of touch and pain in glabrous skin. Conversely, peripheral nerve organization contrasts with higher innervation density and smaller receptive field observed in touch sensors of distal limbs. Taken together, our findings suggest that region-specific morphological organization serves as a fundamental somatotopic mechanism to facilitate regional differences in sensory processing, although distinct organizations were employed by different sensory modalities.
Journal of Dermatological Science Vol 107 (1), July 2022
Yeseul Nho, Katy Lawson, Frane Banovic, and Liang Han
Atopic dermatitis (AD) is one of the most common debilitating inflammatory skin diseases and often results in lifelong burdens for affected patients. Staphylococcus aureus (S. aureus) colonization has been found in the lesional skin of a majority of AD patients and can exacerbate the inflammatory responses. S. aureus secretes a variety of virulence factors such as phenol-soluble modulins (PSMs) to achieve successful colonization and pathogenesis of the bacteria. Our data demonstrate that PSMs can not only induce pain, but also induce itch sensation, suggesting that they contribute to the chronic itch in AD. The pain and itch behavioral responses may partially be due to the direct activation of sensory nerves in the skin. In addition, the PSMs may interact with residential skin cells that can release neuron-stimulating mediators upon activation.
Science Translational Medicine Vol 14 (653), July 2022
Jing Feng, Yonghui Zhao, Zili Xie, Kaikai Zang, Sanja Sviben, Xueming Hu, James A. J. Fitzpatrick, Lu Wen, Yifei Liu, Ting Wang, Katy Lawson, Qin Liu, Yan Yan, Xinzhong Dong, Liang Han, Gregory F. Wu, Brian S. Kim, and Hongzhen Hu
Scratching can temporarily suppress itch sensation. However, persistent scratching can have worsening effects on itch, by triggering the so-called itch-scratch cycle. The mechanisms responsible for this pruritogenic effect remain to be elucidated. Here, Feng et al. showed that the Piezo2 channels in Merkel cells are responsible for the itch triggered by mechanical stimulation in dry skin. In dry, itchy skin, the authors noted a miswiring of nerve endings toward Merkel cells that was absent in normal skin, suggesting that wiring alterations and Merkel cells drive pathological itch-scratch cycle in dry skin.
PNAS Vol 118 (15), April 2021
Haley R. Steele, Yanyan Xing, Yuyan Zhu, Henry B. Hilley, Katy Lawson, Yeseul Nho, Taylor Niehoff, and Liang Han
Chronic itch, associated with dermatologic or systemic diseases, is challenging to treat and significantly affects quality of life. In the past several decades, significant progress has been made to help us understand the mechanisms of itch. Due to the ease of application and analysis, all animal itch behavioral assays utilize pruritogens administered to the hairy skin. However, itch occurs to both hairy and hairless glabrous skin. Many medical conditions such as plantar and palmar psoriasis, dyshidrosis, and cholestasis mainly evoke itch in glabrous skin. We here present evidence demonstrating that distinct neuronal populations are responsible for mediating hairy and glabrous skin itch. This study advanced our understanding of itch and will have significant impact on the clinical treatment of itch.
Neuroscience Letters Vol 744(23), January 2021
Haley R. Steele, Liang Han
Mas-related G protein-coupled receptors (Mrgprs) are a family of receptors implicated in a diverse array of human diseases. Since their discovery in 2001, great progress has been made in determining their relation to human disease. Vital for Mrgprs therapeutic efforts across all disease disciplines is a thorough understanding of Mrgprs signal transduction pathways and polymorphisms, as these offer insights into new drug candidates, existing discrepancies in drug response, and differences in disease susceptibility. In this review, we discuss the current state of knowledge regarding Mrgprs signaling pathways and polymorphisms.
Journal of Investigative Dermatology, October 2020
Yanyan Xing, Haley R. Steele, Henry B. Hilley, Katy Lawson, Taylor Niehoff, Liang Han
Diverse sensory neurons exhibit distinct neuronal morphologies with a variety of axon terminal arborizations used to subserve their functions. Using a novel MrgprC11CreERT2 transgenic mouse line, we labeled a small subset of itch-sensing neurons that express multiple itch-related molecules including MrgprA3, MrgprC11, histamine receptor H1, IL-31 receptor, 5-HT receptor 1F, natriuretic precursor peptide B, and neuromedin B. We found that itch-sensing skin arbors exhibit free endings with extensive axonal branching in the superficial epidermis and large receptive fields. These results revealed the unique morphological characteristics of itch-sensing neurons and provide novel insights into the basic mechanisms of itch transmission.
Journal of Investigative Dermatology, March 2020
Yanyan Xing, Junyu Chen, Henry Hilley, Haley Steele, Jingjing Yang, and Liang Han
Itch, caused by certain groups of sensory neurons, can be a result of dermatological or systemic diseases. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Here we performed RNA sequencing of MrgprA3+ neurons under conditions of contact dermatitis. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main neuronal target for histamine and Mrgprs agonists. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.
Nature Neuroscience Vol 21(3):324-328, March 2018
Liang Han, Nathachit Limjunyawong, Fei Ru, Zhe Li, Olivia J Hall, Haley Steele, Yuyan Zhu, Julie Wilson, Wayne Mitzner, Marian Kollarik, Bradley J Undem, Brendan J Canning, and Xinzhong Dong
Asthma, accompanied by lung inflammation, bronchoconstriction and airway hyper-responsiveness, is a significant public health burden. Mas-related G protein-coupled receptors (Mrgprs) are expressed in a subset of vagal sensory neurons innervating the airway and mediate cholinergic bronchoconstriction and airway hyper-responsiveness. These findings provide insights into the neural mechanisms underlying the pathogenesis of asthma.
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Featured on ScienceDaily, Hopkins Medicine, Science Newsline, and many other sites!
Itch Vol 2(3), December 2017
Yuyan Zhu, Claire E Hanson, Qin Liu, and Liang Han
Other Papers
PNAS Vol 114(10):E1996-E2005, 2017
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Zhe Li, Pang-Yen Tseng, Vinod Tiwari, Qian Xu, Shaoqiu He, Yan Wang, Qin Zheng, Liang Han, Zhiping Wu, Anna L. Blobaum, Yiyuan Cui, Vineeta Tiwari, Shuohao Sun, Yingying Cheng, Julie H. Y. Huang-Lionnet, Yixun Geng, Bo Xiao, Junmin Peng, Corey Hopkins, Srinivasa N. Raja, Yun Guan, and Xinzhong Dong
PLOS One Vol 11(5), 2016
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Eric J. Zaccone, TinaMarie Lieu, Yukiko Muroi, Carl Potenzieri, Blair E. Undem, Peisong Gao, Liang Han, Brendan J. Canning, and Bradley J. Undem
Respiratory Research Vol 17(1):62, 2016
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Amy Y. Chang, Tracy S. Mann, Peter K. McFawn, Liang Han, Xinzhong Dong, and Peter J. Henry
Nature Vol 519(7542):237-241, 2015
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Benjamin D. McNeil, Priyanka Pundir, Sonya Meeker, Liang Han, Bradley J. Undem, Marianna Kulka, and Xinzhong Dong
Annual Review of Biophysics Vol 43:331-355, 2014
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Liang Han and Xinzhong Dong
Nature Neuroscience Vol 16, 174-182, 2013
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Liang Han, Chao Ma, Qin Liu, Hao-Jui Weng, Yiyuan Cui, Zongxiang Tang, Yushin Kim, Hong Nie, Lintao Qu, Kush N Patel, Zhe Li, Benjamin McNeil, Shaoqiu He, Yun Guan, Bo Xiao, Robert H. LaMotte, and Xinzhong Dong
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Reported by The New York Times, The Baltimore Sun, Huffington Post, Daily Mail, and many others!
Neuron Vol 81(4):873-887, 2014
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Yu Shin Kim, Yuxia Chu, Liang Han, Man Li, Zhe Li, Pamela Colleen LaVinka, Shuohao Sun, Zongxiang Tang, Kyoungsook Park, Michael J. Caterina, Ke Ren, Ronald Dubner, Feng Wei, and Xinzhong Dong
Pain Vol 155(8):1613-1621, 2014
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Zhe Li, Shao-Qiu He, Qian Xu, Fei Yang, Vinod Tiwari, Qin Liu, Zongxiang Tang, Liang Han, Yu-Xia Chu, Yun Wang, Niyada Hin, Takashi Tsukamoto, Barbara Slusher, Xiaowei Guan, Feng Wei, Srinivasa N. Raja, Xinzhong Dong, and Yun Guan
Brain Vol 137:1039-1050, 2014
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Lintao Qu, Ni Fan, Chao Ma, Tao Wang, Liang Han, Kai Fu, Yingdi Wang, Steven G. Shimada, Xinzhong Dong, and Robert H. LaMotte
Neuroscience Vol 261:43-51, 2014
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Shaoqiu He, Liang Han, Zhe Li, Qian Xu, Vinod Tiwari, Fei Yang, Xiaowei Guan, Yun Wang, Srinivasa N. Raja, Xinzhong Dong, and Yun Guan
Pain Vol 155(3):534-544, 2013
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Shaoqiu He, Zhe Li, Yu-Xia Chu, Liang Han, Qian Xu, Man Li, Fei Yang, Qin Liu, Zongxiang Tang, Yun Wang, Niyada Hin, Takashi Tsukamoto, Barbara Slusher, Vinod Tiwari, Ronen Shechter, Feng Wei, Srinivasa N. Raja, Xinzhong Dong, and Yun Guan
The Journal of Neuroscience Vol 32:14532-14537, 2012
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Qin Liu, Parul Sikand, Chao Ma, Zongxiang Tang, Liang Han, Zhe Li, Shuohao Sun, Robert H. LaMotte, and Xinzhong Dong
Molecular Brain Vol 4, 40, 2011
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Liang Han, Zhexing Wen, Rachel C. Lynn, Marie-Laure Baudet, Christine E. Holt, Yukio Sasaki, Gary J. Bassell, and James Q. Zheng
Nature Neuroscience Vol 12:848-856, 2009
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Chi Wai Lee, Jianzhong Han, James R. Bamburg, Liang Han, Rachel Lynn, and James Q. Zheng
Journal of Cell Biology Vol 178:107-119, 2007
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Zhexing Wen, Liang Han, James R. Bamburg, Sangwoo Shim, Guo-li Ming, and James Q. Zheng
Journal of Cell Biology Vol 176:101-111, 2007
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Jianzhong Han, Liang Han, Priyanka Tiwari, Zhexing Wen, and James Q. Zheng