The goal of the laboratory is to understand the molecular and cellular 48mechanisms 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 suggested that C-fiber neurons that transmit itch can be broadly divided into three subsets called NP1, NP2 and NP3, which express distinct sets of itch-associated receptor genes. 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 subsets can be specifically manipulated at various stages of disease development. This year we have established and analyzed a mouse strain lacking NP3 sensory neurons, which highly express the receptor for the itch-inducing cytokine IL-31 (Figure). We found that NP3 neurons are impor-tant not only for IL-31-induced itch but also for itch induced by other prurito-gens, such as the mast cell stimulator compound 48/80. By using these mice, we also determined the contribution of NP3 neurons to chronic inflammatory itch caused by repetitive treatment with the active vitamin D3 analogue MC903. In addition, our data suggest that NP3 neurons may have a regulatory role in in-flammation that is exacerbated by the itch-scratch cycle.Figure: Immunofluorescence staining of dorsal root ganglia (DRG) sections from control and NP3-depleted miceIL-31RA and OSMR are the subunits of IL-31 receptor. PGP9.5 is a pan-neuronal marker.Recent Major PublicationsMatsui T, Kadono-Maekubo N, Suzuki Y, Furuichi Y, Shi-raga K, Sasaki H, Ishida A, Takahashi S, Okada T, Toyooka K, Sharif J, Abe T, Kiyonari H, Tominaga M, Miyawaki A, Amagai M. A unique mode of keratinocyte death requires intracellular acidification. Proc Natl Acad Sci U S A 118, e2020722118 (2021)Teratani 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)Invited presentationsOkada T. “Itch induction and regulation of inflammation by IL-31-stimulated sensory neurons” The 51st Annual Meeting of the Japanese Society of Cutaneous Immunol-ogy and Allergy (Tokyo, Japan/Online) November 2021Okada T. “Activation mechanisms of primary sensory neurons transmitting itch” The 30th International Sym-posium of Itch (Online) November 2021Laboratory for Tissue DynamicsTeam Leader: Takaharu Okada
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