RIKEN IMS AnnualReport 2020
51/98

The goal of the laboratory is to understand the molecular and cellular i?simredpesimredβ-alanine receptor MrgprD45mechanisms that underlie tissue homeostasis and its breakdown during disease development. As a most recent focus, we have been studying the func-tion of primary sensory nerves in the skin, with a particular interest in the itch-transmitting nerves. Previous single-cell RNA-sequencing analyses have sug-gested that C-fiber neurons that transmit itch can be broadly divided into three subsets, which express distinct sets of the itch-associated receptor genes (Figure). However, the roles for each subset in the pruritus and inflammation of atopic dermatitis and other skin diseases are incompletely understood. To tackle this problem, we are generating mouse models in which each of the itch nerve sub-sets can be specifically manipulated at various stages of disease development. In addition, we are performing 3D imaging analyses of the itch nerve subsets in the skin and have found that the three subsets innervate different anatomi-cal regions of the skin. Furthermore, this innervation pattern becomes altered in the atopic dermatitis models. We are also investigating gene expression changes in the sensory neurons in atopic dermatitis models by single-cell RNA-sequencing analyses. As a result, we have found that multiple genes potentially responsible for the altered innervation pattern are upregulated or downregu-lated in the subsets of itch neurons. We will continue functional analysis of the itch nerve subsets based on these findings.Figure: Subsets of skin sensory nerves differen-tially express itch-associated receptorsPrevious single-cell RNA-sequencing analysis has sug-gested that sensory neurons expressing itch-associated receptor genes in the mouse dorsal root ganglion can be broadly divided into three subsets, NP1, NP2 and NP3 (Usoskin et al., Nat Neurosci 2015). The NP1 subset in-nervates the epidermis and most of their nerve endings are thought to be located in the epidermis (Zylka et al., Neuron 2005; Olson et al., Elife 2017). The NP2 subset has also been reported to innervate the epidermis, though it is not clear if the majority of their endings are located in the epidermis (Han et al., Nat Neurosci 2013). It is not known whether NP3 innervates the epidermis.Recent Major PublicationsTeratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Shibata S, Miyamoto K, Ishigame H, Chu PS, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H, Inoue M, Yada T, Kitagawa Y, Yoshimura A, Tanida M, Tsuda M, Iwasaki Y, Kanai T. The liver-brain-gut neural arc maintains the Treg cell niche in the gut. Nature 585, 591-596 (2020)Mesin L, Schiepers A, Ersching J, Barbulescu A, Cavazzoni CB, Angelini A, Okada T, Kurosaki T, Victora GD. Restricted clonality and limited germinal center reentry character-ize memory B cell reactivation by boosting. Cell 180, 92-106. e11 (2020)Takahashi S, Ishida A, Kubo A, Kawasaki H, Ochiai S, Nakayama M, Koseki H, Amagai M, Okada T. Homeo-static pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during chronic itch development. Sci Rep 9, 8625 (2019)Invited presentationsOkada T. “Imaging analysis of epidermal sensory nerves and keratinocyte tight junctions” The 58th Annual Meet-ing of the Biophysical Society of Japan, Symposium 2S-7 (Online) September 2020Okada T. “Dynamic homeostasis of epidermal sensory nerves and its breakdown caused by barrier dysfunction” The 119th Annual Meeting of the Japanese Dermato-logical Association, Sponsored Symposium 3 (Online) June 2020NP1IL-4/13 receptorEtc.Chloroquine receptor MrgprA3Pathogenic itch? Inflammation?NP3IL-31 receptorIL-4/13 receptorEtc.Histamine receptor HRH1Cysteinylleukotriene receptor 2NP2Histamine receptor HRH1IL-4/13 receptorEtc.Laboratory for Tissue DynamicsTeam Leader: Takaharu Okada

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