Periostin activates distinct modules of inflammation and itching downstream of the type 2 inflammation pathway

Satoshi Nunomura ¹, Daisuke Uta ², Isao Kitajima ³, Yasuhiro Nanri ⁴, Kosuke Matsuda ², Naoko Ejiri ³, Midori Kitajima ³, Hitoshi Ikemitsu ⁴, Misaki Koga ⁴, Sayaka Yamamoto ⁴, Yuko Honda ⁴, Hironobu Takedomi ⁴, Tsugunobu Andoh ⁵, Simon J Conway ⁶, Kenji Izuhara ⁷

Abstract

Atopic dermatitis (AD) is a chronic relapsing skin disease accompanied by recurrent itching. Although type 2 inflammation is dominant in allergic skin inflammation, it is not fully understood how non-type 2 inflammation co-exists with type 2 inflammation or how type 2 inflammation causes itching. We have recently established the FADS mouse, a mouse model of AD. In FADS mice, either genetic disruption or pharmacological inhibition of periostin, a downstream molecule of type 2 inflammation, inhibits NF-κB activation in keratinocytes, leading to downregulating eczema, epidermal hyperplasia, and infiltration of neutrophils, without regulating the enhanced type 2 inflammation. Moreover, inhibition of periostin blocks spontaneous firing of superficial dorsal horn neurons followed by a decrease in scratching behaviors due to itching. Taken together, periostin links NF-κB-mediated inflammation with type 2 inflammation and promotes itching in allergic skin inflammation, suggesting that periostin is a promising therapeutic target for AD.

Keywords: CP: Immunology; atopic dermatitis; integrin; itching; neutrophil; periostin.

Presenter: Kim Hyein

Yan Chena,c,1, Yuran Songb,c,1 , Huadong Wangd,1 , Yiyun Zhangc,e, Xinyu Huc,f, Kaikai Wangc,e, Yingjin Lua, Zoutao Zhangg, Shuai Lia,c , Anan Lig, Lan Baoa,e,f, Fuqiang Xud, Changlin Lia,c,h,2, and Xu Zhanga,c,e,2

Abstract

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It’s unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal ) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More
than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.

Presenter: Gi Baek Lee

Yongfeng Liu ^# 1 2, Can Cao ^# 1, Xi-Ping Huang ^1 2, Ryan H Gumpper ¹, Moira M Rachman ³, Sheng-Luen Shih ^1 2, Brian E Krumm ¹, Shicheng Zhang ¹, Brian K Shoichet ³, Jonathan F Fay ^4 5, Bryan L Roth ^6 7 8

• PMID: 36302898
• DOI: 10.1038/s41589-022-01173-6

Abstract

The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1-Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.