Central, but not peripheral, nervous system ERK2 is essential for itch signals in murine allergic skin inflammation

Background Itch is a common cutaneous symptom in a variety of dermatological diseases, but detailed neuropathological mechanisms remain to be fully elucidated. This study aimed to assess in vivo ERK2 functions in the nervous system for itch responses. Methods We generated conditional knockout mice d...

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Published in:	Allergy (Copenhagen) Vol. 76; no. 11; pp. 3422 - 3432
Main Authors:	Matsuo, Shinsuke, Hashimoto, Takashi, Matsuura, Fumhiro, Imamura, Osamu, Endo, Shogo, Satoh, Yasushi, Satoh, Takahiro
Format:	Journal Article
Language:	English
Published:	Denmark Blackwell Publishing Ltd 01-11-2021
Subjects:	alloknesis Animals Central nervous system Contact dermatitis Disease Models, Animal Dorsal horn ERK2 Extracellular signal-regulated kinase Histamine Hypersensitivity IL‐31 Immunoglobulin E Inflammation MAP Kinase Signaling System mechanical itch Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinase 1 - genetics Nervous system Neurokinin Neurokinin B Peripheral Nervous System Pruritus Rodents Skin Skin diseases Spinal cord urocortin3 alloknesis urocortin3 mechanical itch ERK2 IL-31
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Summary:	Background Itch is a common cutaneous symptom in a variety of dermatological diseases, but detailed neuropathological mechanisms remain to be fully elucidated. This study aimed to assess in vivo ERK2 functions in the nervous system for itch responses. Methods We generated conditional knockout mice deficient in ERK2 of the central nervous system (CNS) or peripheral nervous system (PNS), respectively, and assessed chemical and mechanical itch responses in vivo. Results Chemical itch responses to histamine, but not to BAM8‐22, were alleviated in CNS Erk2‐deficient mice. In contrast, both histamine‐ and BAM8‐22–induced mechanical itch (alloknesis) were alleviated in CNS Erk2‐deficient mice. Neither chemical itch nor mechanical itch induced by these pruritogens was affected by PNS ERK2 deficiency. Spontaneous scratching behaviors during acute and chronic contact hypersensitivity were impaired in CNS Erk2‐deficient mice, but not PNS Erk2‐deficient mice. In addition, CNS ERK2 deficiency attenuated mechanical itch responses during chronic contact hypersensitivity. Again, PNS Erk2‐deficient mice showed comparable responses of mechanical itch to control mice. In addition, alleviated mechanical itch in CNS Erk2‐deficient mice was observed in IgE‐mediated prurigo‐like allergic skin inflammation. Mechanical itch induced by IL‐31 was also alleviated by CNS ERK2 deficiency. Phosphorylated ERK1/2 was detected in neurokinin B‐expressing cells of the spinal dorsal horn of control mice; these cells accumulated during the induction of chronic contact hypersensitivity. Notably, phosphorylated ERK1/2 was also localized in spinal urocortin3‐expressing neurons that are known to transmit mechanical itch. Conclusions Spinal cord ERK2 could be a potential therapeutic target for intractable itch in pruritic skin diseases. ERK2 deficiency in the central nervous systems resulted in the alleviated chemical itch responses to histamine. Mechanical itch responses induced by pruritogens (histamine, BAM8‐22, and IL‐31) and skin inflammations were also alleviated in central nervous system ERK2‐deficient mice. Neither chemical itch nor mechanical itch was affected by peripheral nervous system ERK2 deficiency. Abbreviations: BAM8‐22, bovine adrenal medulla 8‐22; CHS, contact hypersensitivity reactions; CNS, central nervous system; ERK2, extracellular signal‐regulated kinase 2; KO, knock‐out; PNS, peripheral nervous system; UCN3, urocortin 3
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0105-4538 1398-9995
DOI:	10.1111/all.14867